Pharmaceutical compositions for improved delivery of therapeutic lipophilic actives

ABSTRACT

A solid water-dispersible composition of matter comprising at least one sugar, at least one polysaccharide and at least one surfactant and at least one lipophilic active pharmaceutical ingredient (API), the composition comprises a plurality of micrometric particles each comprising a plurality of lipophilic nanospheres with an average size in the range of 50-900 nm, the at least one lipophilic API is contained in the micrometric particles and is distributed inside and/or outside the lipophilic nanospheres at predetermined proportions, thereby providing an improved delivery of the at least one lipophilic API. A sugar particle comprising a porous sugar material and lipophilic nanospheres having average sizes between 50-900 nm so that the lipophilic nanospheres are comprised within the porous sugar material, the sugar particle comprises at least one edible sugar, at least one edible oil, at least one edible polysaccharide, at least one edible surfactant and at least one lipophilic API.

TECHNOLOGICAL FIELD

The invention relates to compositions and methods that increasebioavailability of therapeutic actives generally characterized as poorlywater-soluble or lipophilic. The compositions and methods of theinvention are designed and adapted for various routes of drug deliveryand can be applicable to a wide range of poorly water-soluble drugs.

BACKGROUND

Modern techniques for drug discovery such as high-throughput in vitroscreening of receptor binding and combinatorial chemistry produce anincreasing number of lipophilic, pharmacologically active compounds(APIs). The overall rate limiting factor in the oral absorption of thesecompounds is predominantly their solubility/dissolution in thehydrophilic intestinal milieu. According to the BiopharmaceuticalClassification System (BCS), lipophilic drugs with low solubility andfavorable permeability characteristics, would be classified as class IIor IV compounds. Some notable examples are glibenclamide, bicalutamide,ezetimibe, aceclofenac, and amphotericin B, furosemide, acetazolamide,ritonavir, paclitaxel.

BCS Class II and IV compounds generally have low oral bioavailability,and as a result frequently fail to proceed to advanced stages of R&D.These types of compounds are not likely be good clinical candidateswithout accompanying development of special formulation methods toovercome problems of solubility or rate of dissolution. Various schemeshave been developed to that end, but not without some major drawbacks.

Surfactants are routinely employed to increase the apparent aqueoussolubility of poorly soluble drugs. Yet, the impact of micellarsolubilization on the intestinal permeability of lipophilic drugs isstill poorly understood. Many studies show that micellar formulations donot always retain their structure in the acidic pH of the stomach forthe time required for their efficient adsorption. More recent researchsuggests that surfactants may have opposing effects on solubility of agiven API and its subsequent intestinal membrane permeability.

Another popular approach to improve solubility relies on use ofcyclodextrin-based formulations. Cyclodextrins are crystalline,non-hygroscopic, cyclic oligosaccharides with a hydrophilic outersurface and a lipophilic central cavity. From pharmaceutical point ofview, cyclodextrins have gained widespread attention and use due totheir ability to interact with poorly water-soluble drugs and increasetheir water solubility. However, a critical review of the literaturereveals that cyclodextrins are not entirely predictable, and that theiruse may lead to counter-intuitive results and even reduction in theadsorption of some APIs.

Overall, for many solubility enhancers, there is a tradeoff betweentheir tendency to improve solubility of lipophilic actives and theirpropensity to have negative effects on the respective intestinalmembrane permeability of the same actives. In other words, a successfuldelivery method is conditioned on careful choice of solubilityenhancer(s) and combinations of other excipients, and their cumulativeimpact on physicochemical and biological properties of the resultingformulations.

Therefore, there is a clear incentive for the development of new andmore progressive formulations of lipophilic actives for overcoming thedrawbacks of solubility/permeability tradeoff. Even more challengingwould be to propose a general and more inclusive approach for improvingbioavailability of various types of lipophilic actives.

There are numerous publications describing certain types of oralformulations with various lipophilic actives in the academic and patentliterature, including those applying nanotechnology. It seems howeverthat none of them is sufficiently inclusive and adaptable so as to beapplicable to a wide range of pharmacologically relevant actives and tothe processes of drug manufacturing.

Certain oral formulations with lipophilic actives were described inWO20035850, WO2015/171445, WO2016/147186, WO2016/135621 andWO2017/180954 with examples of cannabis, or isolated and purecannabinoids, all of which are known for their lipophilicity. Moregeneral examples of formulations with lipophilic APIs using variousnanotechnologies are provided in WO19162951 and WO14176389 as solidformulations, in WO2013/108254 as liquid formulations and in WO0245575and WO03088894 with actives for specific uses in dentistry andcosmetics.

General Description

The primary focus of this invention has been to explore novel strategiesfor improving the permeability and bioavailability of highly lipophilicdrugs. Over the past years, disadvantages of conventional lipid-basedformulations, such as physical instability, limited drug loadingcapacity, passive diffusion, active efflux in the GI tract and extensiveliver metabolism, etc., have been extensively investigated. New lipidicformulations, and specifically the nanostructured lipid carriers, havebeen developed to overcome the barriers that lead to poorbioavailability of lipophilic drugs.

Nanotechnology is an area of rising attention that unwraps newpossibilities for the pharma industry. Nanotechnology is superior to theconventional formulation technologies as regards capabilities to producedrugs with enhanced pharmacological characteristics, a better qualityand safety, and increased shelf life. Today, nanomaterials serve as abasis for qualitative and quantitative production of old and new drugswith enhanced qualities and new types of functionalities.

With respect to poorly water-soluble or lipophilic actives,nano-delivery systems using specific solubility enhancers such asnanoemulsions, dendrimers, nano-micelles, solid lipid nanoparticlesprovide promising strategies for improving solubility, permeation,bio-accessibility, and oral bioavailability overall. Some of thesesystems further provide prolonged, and targeted delivery of actives.

The basic advantage of nanonization is in increasing the substratesurface area and dissolution rate. With lipophilic substances,nanonization can further increase saturation, solubility and reduceerratic absorption, thereby impacting on their transport through the GIwall and increasing their oral bioavailability. In addition, it has beenreported that smaller particles are taken up more easily by macrophages,and thus provide a higher deposition rate and a better therapeuticindex.

Nanoencapsulation of drug/small molecules in nanocarriers is a verypromising approach for development of nanomedicine. Modern drugencapsulation methods allow efficient loading of drug molecules insidethe nanocarriers, thereby reducing the drug-related systemic toxicity.Another application is targeting of nanocarriers to specific tissues andorgans, and thus enhance the accumulation of the encapsulated drug atthe diseased site. Nanoencapsulation can further protect drugs frompremature degradation, and thus increase their stability in thecirculation and tissues.

The present invention makes part of such emerging new technologies. Theinvention applies nanonization technologies to make and manipulatematter on a new size scale, and to create novel structures with highlyunique properties and wide-ranging applications. To that end, theinvention provides an exclusive formulation approach to resolving thespecific problems of solubility and permeability related to lipophilicAPIs, and to improving their bioavailability in vivo by oral and othernon-invasive routes of administration. Importantly, as has beenpresently demonstrated, the formulation approaches of the invention arecompatible with many kinds of lipophilic APIs, and therefore have thepotential of wide-ranging pharmacological applications.

The compositions of the invention constitute a solid microparticulatematter which is fully dispersible in water. This quality, per se,constitutes a significant advantage in terms stability, storage,operability, and applicability to pharma. Other properties of thepresent compositions reside in the specific composition and arrangementof its core components, i.e., the sugars, the polysaccharides, thesurfactants and the lipophilic nanospheres containing APIs inpharmaceutically acceptable oils or oil carriers. The present studiesshow that the oils and actives can be distributed inside and outside thelipophilic nanospheres, which is responsible for the feature ofdifferential bioavailability characteristic of the compositions of theinvention. The sugars, polysaccharides, and surfactants provide aformation or a porous mesh entrapping the lipophilic nanospheres. Theformation or the porosity of the mesh can be modulated by the relativecontent of sugars, polysaccharides, surfactants, and oils, and the sizeof lipophilic nanospheres, which in turn impacts on the microparticulatestructure and texture of the matter as a whole. Advantages of thisparticular structure have been revealed in surprising features ofpreservation of particles size upon dispersion in water, long-termstability, high loading capacity characteristic of the compositions ofthe invention.

Specific examples of the core components of the present compositions aretrehalose, sucrose, mannitol, lactitol and lactose as sugars;maltodextrin and carboxymethyl cellulose (CMC) as polysaccharides; andammonium glycyrrhizinate, pluronic F-127 and pluronic F-68 assurfactants. Regarding oil carriers, the compositions of the inventioncan use natural oils such as those enriched in monounsaturated fattyacids (MUFAs) and polyunsaturated fatty acids (PUFAs), e.g., Omega-3 andOmega-6, or synthetic oils, or mixtures of those.

Thus, the present compositions are essentially hybrid formulationscombining the advantages of lipid-based formulations and nanoparticlesin terms of high loading, long-term stability, reproducibility, enhancedbio-accessibility and oral bioavailability, and other properties. Allthese structural and functional properties of the present compositionsbeen presently explored and exemplified.

More specifically, the key feature of preservation of the nanometricparticle size upon reconstitution of the powder compositions in waterwas found to be consistent throughout various processes of production,storage conditions and various composition of sugars, oils, and actives,and upon fixation to films of polyvinyl alcohol (PVA) and even uponconversion of the compositions into the form of mist (EXAMPLES 1-2, 7,9).

First, the feature of reproducible nanometric size of the lipophilicnanospheres is highly surprising, especially in view of the knowntendency of the nanoemulsion to increase particle size or fuse undervarious conditions. Second, it is compatible with various administrationmodes which can involve drug dispersion and dilution. Third and the mostimportant, it suggests that the benefits of nanonization can bepreserved in the intestinal milieu, with the expected consequences ofhigher solubility, permeability, and bio-accessibility in situ.

Overall, it can be stated that the compositions of the invention provideconsistent loading, entrapment, preservation, and reconstitutioncapacities of lipophilic actives that are preserved through variousexposures, manipulations, and conditions.

The feature of high loading capability was further addressed in a studyshowing that the compositions of the invention can be loaded with APIsin oil carriers up to 90%-95% of the total weight (w/w), this is withoutdisrupting the core characteristics of preservation nanometric size inthe reconstituted powder (EXAMPLE 3).

The feature of chemical preservation of actives was addressed in a studyshowing that the compositions of the invention prevented degradation andoxidation of actives, even with actives sensitive to increasedtemperature, pro-oxidative species, and acidic pH such as lycopene andfish oil (EXAMPLE 2).

Another important feature of the compositions relates to differentdistributions APIs inside and outside the lipophilic nanospheres and theability to increase the encapsulation capacity (EXAMPLES 1.6-1.7) Thisfeature is highly useful in providing compositions with differentialbioavailability for the entrapped and the non-entrapped APIs. Thisfeature was further supported by finding in vivo of bi-phasic releaseprofiles of actives in plasma and tissues characteristic of thecompositions of the invention (EXAMPLE 4).

A biphasic release pattern provides an immediate burst of active releaseand further a prolonged active release. Animals exposed to thecompositions of the invention have shown biphasic release profiles inplasma and tissues, while animals exposed to analogous lipidcompositions showed only immediate release profiles. Due to limitationsof the experimental time frame, the exact duration and nature of theprolonged release profiles (intermittent or sustained) remains to beestablished in future studies.

It can be stated that the immediate, prolonged, and potentially targetedrelease of actives are essential attributes of the present compositions,per se, as they arise from the specific composition and structure oftheir core components. Overall, these features are reflected in improvedoral bioavailability of the present compositions over lipid forms withthe same actives.

The concept of modulation of bioavailability is particularly applicablefor actives which are meant to achieve therapeutic objectives. Modifiedrelease compositions provide chosen characteristics of time courseand/or location of active-release and have the potential to achievedesired therapeutic outcomes. The final products can further includecarriers, excipients, and various types of coating contributing tomodified or targeted release of actives and providing the desiredcharacteristics of consistency and taste to achieve better compliance.

Importantly, the compositions of the invention permit modulation ofrelease profiles by controlling the distribution of APIs inside andoutside the lipophilic nanospheres and thereby controlling theencapsulation capacity of APIs. Encapsulation of APIs is dependent onthe amounts and types of oil carriers and/or the amount and types ofsugars, polysaccharides, and surfactants. It can be further enhanced byremoval of the non-encapsulated oil with hexane, for example.

In other words, the amount and/or the proportion of oil carriers andother components govern the structure and the entrapment capacity of thecompositions regarding lipophilic APIs, which in turn governs theirdifferential availability. Thus, the loading, encapsulation capacity andbioavailability of APIs can be modulated by varying the amounts andproportions of the core components of the compositions.

In practical terms, the compositions of the invention can includevarious distributions and ratios of APIs and oil carriers inside oroutside the lipophilic nanospheres up to the extent of ratios betweenabout 1:0 to 9:1, respectively, and specifically as ratios between about4:1, 7:3, 3:2, 1:1, 3:7 or 1:4, respectively.

Another important feature of the present compositions resides in thefact that they are provided in a solid or semi-solid water dispersibleform. Apart from the advantages in terms of stability and long-termstorage, this feature is highly important when considering oral drugdelivery. The oral route is the route of preference for drug delivery.

It has been further demonstrated that the present formulation approachis applicable to various types of sugars, oil carriers, combinations ofoils and APIs, as single actives, and combinations of actives (EXAMPLES1-11).

More specifically, it was demonstrated that the core properties of thepresent compositions were preserved during various processes ofpreparation, in other words, stemmed from the specific composition ofcore components and not from the process of preparation (EXAMPLE 1.5).

Further, the feature of uniformity and preservation of particles sizeremained consistent upon reconstitution of the compositions incorporatedinto polymeric films (EXAMPLE 7) and in solutions with high osmolaritymimicking the conditions of human skin (EXAMPLE 1.8). This combinationof features makes the present compositions particularly attractive as abase for various dermal, and topical formulations.

In terms of biological properties, the feature of improvedbioavailability has been demonstrated in two independent experiments inanimal models, where the compositions of the invention exhibitedadvantageous patterns of immediate and prolonged release of actives intothe circulation and tissues (EXAMPLES 4-5).

Further, the feature of improved bio-accessibility of actives,indicative of the effective amount of active remaining available foradsorption in the GI, was demonstrated for the compositions of theinvention per se and was further enhanced in compositions incorporatedin enteric-coated capsules (EXAMPLE 6). In other words, the compositionsof the invention were found to be protective against gastric degradationof APIs.

Still further, the feature of improved permeability through variouslayers of the human skin was demonstrated in a set of experimentsshowing that the compositions of the invention had a significantlyenhanced permeation though the 1St and 2nd layers of the stratum corneumcompared to the respective oil forms and were related to a significantlyhigher rate of API penetration to the deeper layers of the skin (EXAMPLE8).

The feature of exceptional adaptability and compatibility of the presentcompositions with various non-invasive modes of administration, apartfrom oral, has been presently demonstrated by incorporating thereconstituted powders into polymeric sublingual, dermal patches (EXAMPLE7), and further, transforming them into the form of mist in an inhaleror nebulizer (EXAMPLE 9); all these, while preserving the core propertyof nanometric particle size.

More recent experiment with lipophilic antibiotics have shown that thepowder compositions of the invention can enhance the efficacy of knownlipophilic antibiotics against pathogenic bacteria, including highlyresistant strains. Moreover, due to the unique properties of smallparticles size and improved solubility, they may have the ability todisrupt and/or enhance the permeability of antibiotic actives throughmicrobial biofilm (EXAMPLE 10).

Overall, the present studies show that the powder compositions of theinvention can protect APIs against various harmful exposures such asduring production and storage and the acidic conditions in the GI, andfurther, can present APIs in a more bioavailable and bio-accessibleforms to the circulation and tissues.

Thus, the presently proposed formulation approach offers a substantialdegree of flexibility and applicability to various types of lipophilicAPIs, or in other words, many of the therapeutic agents belonging to thegroups of BCS Class II and IV compounds. Numerous drugs functioning asenzyme inhibitors, receptor antagonists and agonist, proton-pump andion-channel inhibitors, inhibitors and reuptake inhibitors areclassified as BCS Class II and IV.

A specific application is provided with incorporation of lipophilic APIsinto micronized sugar particles of the invention. Specifically, theinvention provides a smooth finely granulated sugar powder, which initself is a composite particulate material made of a sugar crystallinematrix with entrapped lipophilic nanospheres. This structure confers tothe composite the desired characteristics of sugar (e.g., taste, smallcrystals, larger surface area, higher solubility, mechanic, andthermodynamic stability, etc.) and the ability to entrap lipophilic APIs(EXAMPLE 10). This application is particularly advantageous for certaintypes of actives requiring taste masking.

Ultimately, the powder compositions of the invention have been relatedto properties of higher loading, higher encapsulation capacity, higherstability, modulated release and improved oral bioavailability andbio-accessibility of actives, which significantly exceeded those relatedto analogous lipid-based compositions; this, with a minimumconcentration of surfactants. In addition, in contrast to lipid-basedcompositions where there is a limited play with excipients, thecompositions of the invention permit application of a full range ofexcipients. All these make the compositions of the inventions apromising approach for improving the in vivo properties of lipophilicAPIs, thus making them highly relevant for pharmaceutical and medicalapplications.

BRIEF DESCRIPTION OF THE DRAWINGS

To better understand the subject matter that is disclosed herein and toexemplify how it may be carried out in practice, embodiments will now bedescribed, by way of non-limiting example only, with reference to theaccompanying drawings.

FIG. 1 illustrates the feature of preservation of particle sizecharacteristic of the powder compositions of the invention. Figure showspowder compositions comprising cannabinoids (THC or CBD) stored at 45°C. (oven) for 1, 35, 54, 72 and 82 days (3 months correlates to 24months at RT).

FIG. 2 illustrates the feature of protection of lipophilic activesimparted by the present powder compositions. Figure shows TOTOX (overalloxidation state) values for fish oil (dashed) and the powder compositioncomprising the same (solid). Fish oil is sensitive to oxidation. Figureshows significantly lower levels of the primary and secondary oxidationproducts in the fish oil formulated into the powder composition startingfrom day 0 and up to day 14.

FIGS. 3A-3B illustrate the advantages of improved oral delivery and fastAPIs release in plasma characteristic of the compositions of theinvention (LL-P) compared to lipid-based compositions (LL-OIL) with CBD(3A) and THC (3B) as revealed after single oral dose administration in arat model.

FIGS. 4A-4B reproduce these advantages in a controlled study comparingthe powder compositions (LL-P) with CBD (4A) and THC (4B) andlipid-based compositions with the same APIs (LL-OIL). Figures show aspecific bi-phasing active release profile in plasma characteristic ofthe compositions of the invention.

FIGS. 5A-5D show that the advantages of improved oral bioavailabilityare reproduced in tissues of animals administered with the powdercompositions (LL-P) with THC and CBD and lipid-based compositions withthe same APIs (LL-OIL). Figures show bi-phasing active release profilein the liver and brain characteristic of the compositions of theinvention.

FIG. 6 shows that the advantages of improved oral delivery andbioavailability are applicable to a wide range of lipophilic actives.Figure shows actives release profile in plasma of the powder Vitamin D3composition (solid) vs. the analogous lipid composition (dashed) uponsingle oral dose administration in a rat model. The powder compositionshows a 2-fold increase in the concentration of Vitamin D3 over thelipid composition.

FIG. 7 illustrate the feature of enhanced bio-accessibility (degree ofGI digestion) characteristic of the compositions of the invention usingsemi-dynamic in vitro digestion model. Figure show enhancedbio-accessibility of two APIs found in Oregano, Thymol and Carvacrol, ofthe powder compositions (P) compared to the respective oil forms (O),for each API and total APIs.

FIGS. 8A-8D further expand on the advantages of improvedbio-accessibility using semi-dynamic model. Figures show that theprotective effect and bio-accessibility of the powder composition can befurther enhanced with enteric coated capsule (solid) compared the powdercomposition alone (dashed) and the oil-based composition (dotted).Figure relates to the bio-accessibility of total Thymol and Carvacrol(A), Carvacrol (B) and Thymol (C) at the end of the gastric phase, andthe bio-accessibility of total Thymol and Carvacrol in the powdercomposition with enteric coated capsule (D) during the gastric andduodenal phases.

FIG. 9 illustrates the advantage of improved permeability through thefull thickness of human skin as revealed in ex vivo model. Figure shows6-fold increase in the permeability of Vitamin A in the powdercomposition compared to the lipid composition with the same API.

FIGS. 10A-10C show analogous experiment with respect to the permeabilityof CBD in the powder composition and lipid composition through the1^(st) outermost layer of the stratum corneum (A), 2^(nd) layer of thestratum corneum (B), and a significantly higher cumulative transport ofCBD into the deeper layers of the skin, overall (C).

FIGS. 11A-11B are SEM images (scanning electron microscope) undermagnification ×1K (A) and ×5K (B) showing sugar particles with Theobromaoil with the characteristic smooth, finely granulated texture, and sizein the range of 20-50 μm.

FIGS. 12A-12D illustrate the composite nature of the sugar particle ofthe invention. Figures are cryo-TEM images (cryogenic transmissionelectron microscopy) showing lipophilic nanospheres of average size of80-150 nm entrapped in the sugar particle.

DETAILED DESCRIPTION OF EMBODIMENTS

It should be appreciated that the invention is not limited to specificmethods, and experimental conditions described herein, and that theterminology used herein is for the purpose of describing specificembodiments is not intended to be limiting.

Effective oral delivery of drugs is extremely influenced by aqueoussolubility and intrinsic dissolution rate. Dissolution is the mainrate-limiting step in the absorption of BCS Class II or IV drugs,together with additional factors such as hepatic first pass metabolism,drug efflux by P-gp, intra-enterocyte metabolism and chemical andenzymatic degradation.

When a poorly water-soluble drug enters the GI, a series of events limitits absorption: First, biliary secretions in the upper part of the GIplay a role in the solubilization and emulsification of such drugs viaformation of micelles, whereby it is presented to the absorptivemembrane of the enterocyte in a more bio-accessible form. The capabilityof this process, however, is very limited and variable.

Second, the unstirred water layer (UWL), which separates the enterocytesbrush border (atypical membrane) from the bulk fluid of the intestine,is a major hydrophilic barrier for the absorption of lipophiliccompounds.

Third, in the enterocyte, there are biochemical barriers that affectdrug absorption. CYP 3A4 (CYP3A4) enzymes in the enterocyte endoplasmicreticulum are responsible for a major part of drug metabolism in theintestinal wall. Studies have shown it to be a major barrier to theabsorption of lipophilic drugs.

Four, drug efflux transporters located in the apical enterocytemembrane, such as P-gp, are also responsible for poor oralbioavailability of various drugs (e.g., digoxin, paclitaxel,doxorubicin, atorvastatin etc.). Apical P-gp efflux pumps, the mostcomprehensively studied transporters, reduce drug absorption bytransporting the drug from the enterocyte back to the intestine. Thereis a link between CYP3A4 enzymes and the P-gp activities in working inconcert to reduce the bio-accessibility of lipophilic drugs.

Five, after the intra-enterocyte metabolism, the P-gp efflux and beforereaching the systemic circulation, the drug is transferred to the liverwhere it is exposed to various metabolic enzymes. This first passhepatic metabolism is another significant barrier to the absorption oflipophilic drugs (e.g., β-blockers, calcium channel blockers andothers).

Considering the above pharmacokinetic and pharmacodynamic obstacles,there is a pressing need in the design novel formulations increasingoral bioavailability of poorly water-soluble or lipophilic drugs.

Many researchers and pharma industries are developing various deliverysystems basing on different nanoemulsion fabrication methods. One of themain disadvantages of nanoemulsions, in general, is their relativeinstability in terms of particles size over time. The nanoemulsions insolid powder forms, in particular, are known for lack of uniformity inparticle size, and specifically after reconstitution in water. Inaddition, there is a general tendency to increase particle size due tofusion of particles under various conditions.

An increased particle size and lack of uniformity lead to significantvariability in the absorption of substances entrapped in thenanoparticles, and poor oral bioavailability. Larger particles have asmaller surface area, and thus, an inferior absorption in plasma andtissues. Therefore, despite the potential of the nanoemulsiontechnology, there are still significant drawbacks with its incorporationinto the pharma industry.

The present invention has proved to surpass these difficulties withnanonized powder compositions of lipophilic APIs, which while beingreadily dispersible in water preserve properties of loading,encapsulation and storage potential and improved oral bioavailability.

In the broadest sense, the compositions of the invention can bearticulated as solid water-dispersible compositions of lipophilic activepharmaceutical ingredients (APIs). Importantly, due to the solid orsemisolid constitution and the ability to produce homogenous dispersionsin water, the present compositions are especially advantageous forlong-term storage, preservation, and oral delivery, among others.

In numerous embodiments the compositions of the invention are provided aform of water-dispersible powders.

With respect to the actives, the term ‘active pharmaceutical ingredient(API)’ refers herein to any substance falling under the definition byWHO, i.e., substances intended to furnish pharmacological activity or tootherwise have direct effect in the diagnosis, cure, mitigation,treatment, or prevention of disease, or to have direct effect inrestoring, correcting, or modifying physiological functions in humanbeings.

In numerous embodiments the compositions of the invention comprise oneor more lipophilic API dissolved in an oil carrier or a pharmaceuticallyacceptable oil.

The term ‘lipophilic API’ requires additional attention. Lipophilicityrefers to the ability of a chemical compound to dissolve in fats, oils,lipids, and non-polar solvents. Lipophilicity, hydrophobicity, andnon-polarity describe the same tendency, although they are notsynonymous. Lipophilicity of uncharged molecules can be estimatedexperimentally by methods measuring the partition coefficient (logP) ina water/oil biphasic system. For molecules that are weak acids or bases,the measurements must further consider the pH wherein the majority ofspecies remain uncharged.

A positive value for logP denotes a higher concentration in the lipidphase.

Thus, in numerous embodiments, the invention applies to uncharged orweekly charged lipophilic API having a partition coefficient (logP) ofmore than 0.

More specifically, the invention is applicable to any lipophilic APIwith logP in the range between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8,8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18,18-19, 19-20, or more.

The term ‘lipophilic API’ further relates certain classes of BCS drugsin relation to the four known categories by their solubility andpermeability properties: Class I compounds with higher solubility andpermeability; Class II with lower solubility but higher permeability;Class III with higher solubility but less permeability; and Class IVcompounds with the lowest counts of solubility and permeability index.

Thus, in numerous embodiments, the compositions of the invention areparticularly applicable to BCS Class II and IV compounds.

In some embodiments, the present compositions are applicable to BCSClass II compounds.

From another point of view, the compositions of the invention can beseen as a composite matter comprising a plurality of micrometricparticles each comprising a plurality of lipophilic nanospheres with anaverage size in the range of about 50 nm to about 900 nm, the at leastone lipophilic API is contained in the micrometric particles and isdistributed inside and/or outside the lipophilic nanospheres atpredetermined proportions, thereby providing improved delivery of the atleast one lipophilic API.

In other words, the compositions of the invention are a solidparticulate matter comprising particles at a micrometric scale, orparticles with an average size in a range of between about 10-900 μm, ormore specifically with an average size in the range of 10-100 μm,100-200 μm, 200-300 μm, 300-400 μm, 400-500 μm, 500-600 μm, 600-700 μm,700-800 μm and 800-900 μm.

In certain embodiments the powders of the invention can compriseparticles with an average size in a range of between about 10 μm and toabout 300 μm, or more specifically with an average size in the range of10-50 μm, 50-100 μm, 100-150 μm, 150-200 μm and 250-300 μm.

The micrometric particles of the compositions of the invention, inthemselves, are a composite matter comprising lipophilic nanosphereswith an average size between about 50-900 nm, and more specifically, anaverage size in a range between about 50-100 nm, 100-150 nm, 150-200 nm,200-250 nm, 250-300 nm, 300-350 nm, 350-400 nm, 400-450 nm, 450-500 nm,500-550 nm, 550-600 nm, 650-700 nm, 700-750 nm, 750-800 nm, 800-850 nm,850-900 nm and 900-1000 nm (herein an average size is an averagediameter).

The size or diameter of the lipophilic nanospheres can be measured byDLS (dynamic light scattering) upon reconstitution of the powdercomposition in water, such measurements have been presently exemplified.

In numerous embodiments the size of the micrometric particles correlatesto the size of the lipophilic nanospheres, meaning that the size of thelipophilic nanospheres governs the size of the of the micrometricparticles.

The above implies that the lipophilic nanospheres are essentiallyentrapped in the micrometric particles. It further implies that thiscomposite matter has certain porosity or arrangement permitting tocontain the nanospheres. These two features have been presentlyexemplified. They are further reflected in the loading and theencapsulation capacity characteristic of the compositions of theinvention (see below)

An important feature of the invention is that the shape and size of thelipophilic nanospheres are substantially maintained upon dispersion inwater. In other words, due to particular composition and structure ofthe composite matter, the average size of the nanospheres remainsunchanged under various conditions such as lyophilization, long-termstorage, fixation and release from matrixes or films such as PVA, etc.The term ‘substantially maintained’ herein implies a deviation of 1-5%,5-10%, 10-15%, 15-20% or up to 25% in average diameter before and afterthe manipulation or exposure to certain conditions.

An important feature of the present compositions resides in thedistribution of the lipophilic APIs inside and outside the lipophilicnanospheres. This feature is responsible for the properties of immediateand/or prolonged delivery or of release of actives characteristic of thecompositions of the invention.

In numerous embodiments the lipophilic APIs can be distributed inside oroutside the lipophilic nanospheres at a ratio of between about 1:0 to9:1, respectively.

In certain embodiments the lipophilic APIs can be distributed inside oroutside the lipophilic nanospheres at a ratio of between about 4:1, 7:3,3:2, respectively, meaning that they are present in an excess inside thelipophilic nanospheres.

In other embodiments the lipophilic APIs can be distributed inside oroutside the lipophilic nanospheres at a ratio of between about 3:7 or1:4, respectively, meaning that they are present in an excess outsidethe lipophilic nanospheres.

In still other embodiments the lipophilic APIs can be distributed insideor outside the lipophilic nanospheres at the ratio of about 1:1, meaningthat they are present in approximately equal proportions inside andoutside the lipophilic nanospheres.

The same feature can be further articulated in terms of encapsulationcapacity of the lipophilic APIs into the compositions. The term‘encapsulation capacity’ refers to the amount or a proportion oflipophilic APIs entrapped inside the particulate matter, or the powdercomposition as a whole.

In numerous embodiments the compositions of the invention can have anencapsulation capacity of lipophilic APIs up to at least about 80% (w/w)relative to total weigh, or more specifically up to at least about 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% and 98% (w/w), orin the range between about 50%-98%, 60%-98%, 70-98%, 80-98% and 90-98%(w/w) relative to total weigh.

This feature is further related to loading capacity of the lipophilicAPIs onto the compositions. The term ‘loading capacity’ refers to theamount or a proportion of lipophilic APIs that are loaded onto thepowder composition.

In numerous embodiments the compositions of the invention can have aloading capacity of lipophilic APIs up to at least about 80% (w/w)relative to total weigh, or more specifically up to at least about 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% and 98% (w/w), orin the range between about 50%-98%, 60%-98%, 70-98%, 80-98% and 90-98%(w/w) relative to total weigh.

Another important feature characteristic of the present compositions islong-term stability or an extended shelf-life. This feature encompassesherein structural, chemical, and functional stabilities. In thisinstance, the structural stability is reflected in the ability topreserve particle size of the nanospheres upon reconstitution in water.The chemical stability reflects protection against degradation andoxidation under temperature, light and acidic pH, for example. Thefunctional stability is reflected in preservation of properties ofimmediate and prolonged actives release.

In numerous embodiments the compositions of the invention can have along-term stability of about at least about 1 year at room temperature,or more specifically up to at least about 6 months, 1 year, 2, years, 3years, 4 years, 5 years at room temperature.

With respect to core components, in general, the compositions of theinvention comprise at least one sugar, at least one polysaccharide andat least one surfactant and at least one lipophilic API.

In numerous embodiments the lipophilic APIs can be dissolved in at leastone oil carrier or a pharmaceutically acceptable oil.

In other embodiments the lipophilic APIs in themselves can constitute anoily substance or a pharmaceutically acceptable oil.

Examples of booth these types of actives have been presently provided(EXAMPES 1-9).

As has been noted, the oil and the other core components are essentiallyresponsible for the arrangement and porosity of the composite matter,and together with the oil component impact on the features ofpreservation of particle size, loading and encapsulation capacitycharacteristic of the present compositions.

The term ‘pharmaceutically acceptable oil’ encompasses herein to any oilthat is generally safe, non-toxic, or biologically undesirable, and thatwhich is acceptable for use in humans. The oils comprised in thecompositions of the invention can be broadly characterized as non-toxicoils for food and pharmaceutical industry regulated by the FDA or EMA,or classified as GRAS (Generally Recognized As Safe).

In numerous embodiments the pharmaceutically acceptable oils can beobtained from a vegetable or an animal source, a synthetic oil or fat,or a mixture thereof.

In numerous embodiments the pharmaceutically acceptable oils can benatural oils, synthetic oils, modified natural oils, or combinationsthereof.

In certain embodiments, the pharmaceutically acceptable oils can beselected from acylglycerols, mono- (MAG), di- (DAG) and triacylglycerols(TAG), medium-chain triglycerides (MCT), long chain triglycerides (LCT),saturated or unsaturated fatty acids.

In numerous embodiments the compositions of the invention can comprisepharmaceutically acceptable oils from plant or animal sources. Forexample, oils comprising a substantial proportion of monounsaturatedfatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) would beadvantageous in terms of additional health benefits.

In certain embodiments the pharmaceutically acceptable oils can beselected from the group of Omega oils, such as Omega 3, Omega 6, Omega 7and Omega 10, or combinations thereof. Omega-3 and Omega 6 fatty acidsplay crucial role in brain function, normal growth and development.Omega-6 types help stimulate skin and hair growth, maintain bone health,regulate metabolism and reproductive system.

In certain embodiments, the pharmaceutically acceptable oil can be hempoil, alone or in combination with other oils. Hemp oil contributes toskin regeneration.

Thus, from a broader perspective, the compositions of the invention cancomprise any pharmaceutically acceptable type of vegetable oils, animaloils or fats, or essential oils. A nonlimiting list of relevant oils isprovided in ANNEX A.

With respect to sugars, the sugars that are applicable to the presentcompositions can be broadly characterized as short chain carbohydratesand sugar alcohols, and more specifically oligo-, di-, monosaccharidesand polyols. Sugars are safe and are ubiquitously used thepharmaceutical industry. The sugars can be from natural sources orsynthetic.

In numerous embodiments the sugars can be selected from trehalose,sucrose, mannitol, lactitol and lactose.

In other embodiments the sugars can be xylitol, sorbitol, maltitol.

The relevant polysaccharides can be broadly characterized aspolysaccharides suitable for use in pharmaceutical industry andgenerally considered as safe. They can be natural and/or syntheticpolysaccharides. Specific examples of natural polysaccharides arefructans found in many grains and galactans found in vegetables, andfurther methyl-, carboxymethyl- and hydroxypropyl methyl-celluloses, andalso pectin, starch, alginate. A nonlimiting list of relevantpolysaccharides is provided in ANNEX A.

In numerous embodiments the polysaccharides can be selected frommaltodextrin and carboxymethyl cellulose (CMC).

The relevant surfactants can be broadly characterized as non-toxicsurfactants suitable for use in pharmaceutical industry, andspecifically nonionic and anionic surfactants. Examples of anionicsurfactants include (a) carboxylates: alkyl carboxylates-fatty acidsalts; carboxylate fluoro surfactants, (b) sulfates: alkyl sulfates(e.g., sodium lauryl sulfate); alkyl ether sulfates (e.g., sodiumlaureth sulfate), (c) sulfonates: docusates (e.g., dioctyl sodiumsulfosuccinate); alkyl benzene sulfonates, (d) phosphate esters: alkylaryl ether phosphates; alkyl ether phosphates. Sodium lauryl sulphate BP(a mixture of sodium alkyl sulfates, mainly sodium dodecyl sulfate,C₁₂H₂₅SO₄ ⁻Na⁺). The non-ionic surfactant can include polyol esters,polyoxyethylene esters, poloxamers. Polyol esters include glycol andglycerol esters and sorbitan derivatives. Fatty acid esters of sorbitan(Spans) and their ethoxylated derivatives (Tweens, e.g., Tween 20 or 80)are commonly used non-ionic surfactants. A nonlimiting list of relevantsurfactants (or emulsifiers) is provided in ANNEX A.

The most frequently used surfactants in the pharmaceutical industry arePolysorbate 20 and 80, and Poloxamer 188 in a concentration range of0.001% to 0.1%.

In numerous embodiments the surfactants can be selected from ammoniumglycyrrhizinate, pluronic F-127 and pluronic F-68.

In other embodiments the surfactants can be selected frommonoglycerides, diglycerines, glycolipids, lecithins, fatty alcohols,fatty acids or mixtures thereof.

In other embodiments the surfactants can be sucrose fatty acid esters(sugar ester).

In numerous embodiments the compositions of the invention can compriseany combination of the above component, with more than one agent fromthe above groups.

With respect to APIs, as has been noted, present compositions encompassa wide range of actives. The relevant APIs can be broadly classified onthe basis of their functionality, e.g., enzyme inhibitors, receptorantagonists, agonists, proton-pump and ion-channel inhibitors and/orreuptake inhibitors. Examples of lipophilic APIs belonging to thesegroups are Angiotensin-Converting Enzyme (ACE) inhibitors used for thetreatment of hypertension, Selective Serotonin Reuptake Inhibitors(SSRIs) used in a wide range of psychiatric contexts, and Retinoid XReceptor (RXR) agonists used for the treatment of cancer, all of whichare highly lipophilic.

Alternatively, the relevant APIs can be classified as antibiotics,antifungal, antiviral drugs, neuroleptics, analgesics, hormones,anti-inflammatory drugs, non-steroidal anti-inflammatory drugs,anti-rheumatic, anticoagulant drugs, beta-blockers, diuretica,anti-hypertension drugs, anti-atherosclerosis and antidiabetic drugs,anti-asthmatic drugs, decongestants, cold medicines. Examples of arelipophilic agents from these groups are synthetic opioids such asPethidine, nonsteroidal anti-inflammatory drugs (NSAID) such asFlurbiprofen and Ibuprofen, antibiotics such as Rifarnpicin which ishighly lipophilic, and statins such as Torvastatin, Simvastatin,Lovastatin.

In other words, the main criterion for the selection of candidate APIsfor the present compostions is lipophilicity. Thus, the candidatelipophilic APIs can be from one of more of the general drug categoriesdefined by the FDA. A nonlimiting list of relevant groups of drugs isprovided in ANNEX A.

It should be noted that the compositions of the invention are furtherapplicable to other lipophilic actives such as nutraceuticals, vitamins,dietary supplements, nutrients, antioxidants, and others, which can beintroduced into the composition together with the lipophilic APIs.

As has been noted, in numerous embodiments, pharmaceutically acceptableoil, per se, can be characterized as nutraceuticals, vitamins, dietarysupplements, nutrients and antioxidants. Example of such oils are Omegaoils and fish oil exemplified on this application.

More generally, in numerous embodiments the lipophilic APIs canconstitute between about 10% to about 98% of the compositions of theinvention (w/w), or more specifically between about 10%-20%, 20%-30%,30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90% and 90%-98% of thepresent compositions (w/w), or up to about 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90% and 98% of the present compositions (w/w).

On the other hand, in numerous embodiments the sugars can constitutebetween about 10% to about 90% of the compositions of the invention(w/w), or more specifically between about 10%-20%, 20%-30%, 30%-40%,40%-50%, 50%-60%, 60%-70%, 70%-80%, and 80%-90% of the presentcompositions (w/w), or up to about 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90% of the present compositions (w/w).

Further, in numerous embodiments the present compositions can furthercomprise carriers, excipients, and additives for purposes of color,taste, and specific consistencies. The terms ‘carriers and excipients’encompass herein any inactive substances that serve as the vehicle ormedium for APIs and oils comprised in the compositions.

Another important feature of the compositions of the invention is theability to provide an improved delivery of lipophilic APIs. The term‘improved delivery’ encompasses herein improved drug solubility, drugabsorption or drug release by any pharmacokinetic or pharmacodynamicparameters to provide improved oral, topical, dermal and transdermalbioavailability or drug delivery via any other route.

The notion of improved delivery has been based on the findings ofsuperior pharmacokinetic and pharmacodynamic properties of the presentcompositions in plasma and tissues, upon oral administration (EXAMPLES4-5) and topical application (EXAMPLE 8).

The term ‘improved’ encompasses herein a change in a range of about5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 45-50%, 50-55%,55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%relative to oil forms with the same actives, or up to 2, 3, 4, 5, 6, 7,8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 fold relative to oil formswith the same actives.

This term further encompasses any advantageous change in drug release,permeability or absorption patterns, including the ability to modulatethese patterns such as those revealed in the present compositions.

Thus, in numerous embodiments the compositions of the invention canprovide an immediate release of lipophilic APIs to one or more parts ofthe GI tract, plasma or one or more tissues.

The term ‘immediate release’ implies that the lipophilic API can bemeasured in the GI or plasma within a relatively short period of time,such as after 1, 10, 20, 30, 40, 50, 60 min from the oraladministration. It further implies a burst or a temporary release of APIin the GI or plasma. The term further applies to the levels of API inorgans or tissues (although with a slightly delayed timing), such aswithin 10, 20, 30, 40, 50, 60, 70, 80, 90 min from the oraladministration thereof via oral or any other route.

In other embodiments the compositions of the invention can provide aprolonged release of lipophilic APIs to a part of the GI tract, plasmaand/or tissues.

The term ‘prolonged release’ implies that active is measured in the GI,plasma and tissues with a lag, such as after 30, 60, 90, 120 min fromthe oral administration, and persists in the GI, plasma and tissues for2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h and more after the oraladministration.

This term further encompasses situations wherein API increasescontinuously, or increases and reaches a plateau, and increases in oneor more temporary bursts.

In other embodiments the compositions of the invention can provide abiphasic release comprising an immediate and a prolonged release oflipophilic APIs to a part of the GI tract, the plasma and/or tissues.

In certain embodiments the compositions of the invention provideimmediate and/or prolonged release of lipophilic APIs to one or moretissues of the central nervous system (CNS).

In certain embodiments the compositions of the invention provideimmediate and/or prolonged release of lipophilic APIs to lymphatictissues, one or more part of the GI and/or the liver.

The feature of improved delivery of actives is directly related toimproved oral bioavailability. Thus, in numerous embodiments thecompositions of the invention provide improved oral bioavailability oflipophilic APIs compared to analogous oil forms. This feature has beenpresently exemplified with respect to various types of compositions ofthe invention.

Further, in numerous embodiments the compositions of the inventionprovide an improved bio-accessibility of lipophilic substances comparedto analogous oil forms. The term ‘ bio-accessibility’ refers herein toan amount of API released in the GI tract and becoming available foradsorption (enters the bloodstream), it is further dependent ondigestive transformations of API into a material ready for absorption,the absorption into intestinal epithelial cells and the pre-systemic,intestinal, and hepatic metabolism.

In numerous embodiments the compositions of the invention can furtherprovide an improved permeation of lipophilic APIs into one or more partof the GI tract or one or more tissues compared to analogous oil forms.

Modulation of biological properties of a dug such as drug delivery,bioavailability, bio-accessibility and permeation can have significantimpact on the potential to achieve desired therapeutic outcomes orbetter patient compliance.

More specifically, modulation of these properties can have significantimpact on therapeutically effective dosing, the number of administrationand the overall drug regimen.

The term ‘therapeutically effective amount’ (also pharmacologically,pharmaceutically, or physiologically effective amount) broadly relatesto an amount of API needed to provide a desired level physiological orclinically measurable response. Analogous terms are ‘therapeutic dose’or ‘therapeutically effective dose’ relate to doses of API in apharmaceutical composition or a dosage form, which can produce animprovement/reduction of at least one symptom of a disorder, a diseaseor a condition.

With respect to the therapeutically effective doses, the presentformulation approach provides an exceptional flexibility, and capacitiesof encapsulation and loading of various amounts of APIs. Due of thewide-ranging applicability of the present composition to various typesof APIs, the effective amounts of can expressed by ways of proportions.

In numerous embodiments, the therapeutically effective amount oflipophilic APIs and other actives comprised in the compositions can bein the range between about between about 10% to about 98% of thecomposition (w/w), or more specifically between about 10%-20%, 20%-30%,30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90% and 90%-98% of thepresent compositions (w/w), or up to about 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90% and 98% of the present compositions (w/w).

Therapeutically effective amount or dose can be further expressed as adose of API per single dosage form and/or per single administration, andfurther as a daily or a weekly dose implying multiple administrations.

With respect to therapeutic effect, an improvement or alleviation ofsymptoms o a disorder or a condition can be evaluated by one or more ofthe following parameters: a type and/or a number of symptoms, severity,frequency of symptoms, specific groups of symptoms (partial symptoms),and/or overall manifestation of symptoms in a subject or a group. Theeffect can be further expressed as a proportion of reduction on aseverity scale, e.g., up to about 5%, 10%, 15%, 20%, 25%, 50%, 75%, 100%reduction of a symptom(s), or a complete abolition of symptom(s).

These parameters are further dependent on the specific API, and patientspecific factors such pre-existing condition, compliance, etc. Theyimply estimates produced on individual basis (case-by-case) andestimates on population basis (clinical trial).

The mechanisms by which the compositions of the invention exert improvedoral bioavailability are yet to be discovered. One can assume that thespecific combination and structure of the core components and particlescan contribute to one or more of the following mechanisms:

-   -   The lipophilic components can contribute to biliary secretion        and emulsification of API. Various lipids have been shown to        induce biliary secretion in the upper part of GI and enhance        emulsification dependent drug absorption, thus improving        bioavailability.    -   The nanospheres can facilitate the passage of API across UWL. It        has been shown that the nanometric particle size improves the        surface area, thereby improving the dissolution of hydrophobic        drugs in UWL.    -   The encapsulation into nanoparticles protects API from enzymatic        degradation. It has been shown that encapsulated drugs are less        exposed to enzymatic degradation during absorption process and        can stay for a longer time in the intestinal lumen in vivo.    -   It has been shown that certain lipid excipients and surfactants        are capable of inhibiting P-gp-mediated drug efflux and have the        potential to alter the pharmacokinetics profile of API in vivo.    -   Certain lipids and oils can further stimulate lymphatic        transport, thereby providing a way to bypass the hepatic        metabolism. Thus, for drugs that are extensively metabolized on        the first pass through the liver, the lymphatic route can        provide rescue and significantly enhance their bioavailability.

Thus, the presently proposed platform can provide a comprehensive andinclusive approach to design and development of novel formulations oflipophilic drugs with improved qualities of bioavailability, tissuedistribution and short- and long-term effects.

The present compositions can be further characterized in terms ofadministration modes. In numerous embodiments the compositions of theinvention can be adapted for oral, sublingual, or buccaladministrations.

In other embodiments the compositions of the invention can be adaptedfor rectal, topical, dermal or transdermal administrations.

Yet in other embodiments the compositions of the invention can beadapted for inhalation or nebulization. These specific applications havebeen recently exemplified.

In numerous embodiments, the compositions can comprise coatings andpackage forms contributing to long term storage, stability, and otherproperties. Use of enteric-coated capsules and their role in enhancingthe bio-accessibility of the compositions of the invention has beenpresently exemplified.

In numerous embodiments the compositions can comprise one or morecarriers and/or one or more coatings.

Gastro-resistant and controlled release coatings are especiallyapplicable to oral dose forms. Such coatings can be achieved by variousknown technologies, such as the use of poly(meth)acrylates or layering.A well-known example of poly(meth)acrylate coating is EUDRAGIT®. Apartfrom increasing actives effectiveness, poly(meth)acrylate coatingfurther provides protection from external influences (moisture) ortaste/odor masking to increase compliance.

The layering encompasses herein a range of technologies using substancesapplied in layers as a solution, suspension (suspension/solutionlayering) or powder (dry powder layering). Various characteristics canbe achieved by use of supplementary materials.

It should be noted that certain types of coating can further enhancetargeting to specific tissues and organs.

In other words, one of advantages of the present technology is itsability to provide a flexible product that can be adapted to variouspharmaceutical technologies.

All the above further apply to the methods, dosage forms and a varietyof other applications of the invention to pharmaceutical industry.

More specifically, it is another objective of the invention to provide adosage form comprising a therapeutically effective amount of thecompositions according to the above.

In numerous embodiments the oral dosage forms of the invention can beprovided in the form of tablets or capsules.

Thus, in numerous embodiments the oral dosage forms of the invention cancomprise a coating, a shell, or a capsule.

As has been noted, in numerous embodiments the coating, shell or capsulecan contribute to the prolonged delivery of the lipophilic APIs.

In numerous embodiments the coating, shell or capsule contribute toenhanced bio-accessibility of the lipophilic APIs.

In numerous embodiments the dosage forms can comprise additionalcarriers, excipients, and other additives for purposes of color, tasteand specific consistencies.

In numerous embodiments the dosage forms can be adapted for oral,sublingual, buccal, rectal, topical, dermal, or transdermaladministrations.

In numerous embodiments the dosage forms can be adapted for inhalationor nebulization.

In certain embodiments the dosage forms can be in a form of sublingual,dermal or transdermal patches. Such patches using PVA plasticizingmaterial have been presently exemplified.

For this specific application, the suitable plasticizing materials canbe generally characterized as non-toxic water dissolvable materials.Specific examples can include but, are not limited to, synthetic resinssuch as polyvinyl acetate (PVAc) and sucrose esters and natural resinssuch as rosin esters (or ester gums), natural resins such as glycerolesters of partially hydrogenated rosins, glycerol esters of polymerisedrosins, glycerol esters of partially dimerised rosins, glycerol estersof tally oil rosins, pentaerythritol esters of partially hydrogenatedrosins, methyl esters of rosins, partially hydrogenated methyl esters ofrosins and pentaerythritol esters of rosins. Also, synthetic resins suchas terpene resins derived from alpha-pinene, beta-pinene, and/ord-limonene and natural terpene resins may be applied in the chewy base.

The invention can be further articulated by way of pharmaceuticalcompositions comprising the compositions according to the above, andoptionally further comprising pharmaceutically acceptable carrier(s)and/or excipient(s).

From yet another point of view the invention provides a kit comprisingone or more dosage form according to the above, and optionally furthercomprising a device for administering thereof.

In certain embodiments the kit of the invention can include an inhaleror a nebulizer. This application is particularly relevant to thecompositions provided in the form of mist in the context of variouspulmonary conditions such as asthma.

From another point of view, the invention provides compositions anddosage forms according to the above for use in improving the oralbioavailability of at least one lipophilic APIs comprised in therespective compositions or dosage forms.

From yet another point of view, the invention provides compositions anddosage forms according to the above for use in improving thebio-accessibility at least one lipophilic API comprised in therespective compositions or dosage forms.

Still from another point of view, the invention provides a series ofmethods for improving the oral bioavailability and/or thebio-accessibility of at least one lipophilic API for treating a disorderor a condition in a subject in need thereof, the main feature of suchmethods is administering to the subject therapeutically effectiveamounts of the compositions and dosage forms of the invention.

It is another objection of the invention to provide methods for treatingor alleviating disorders or clinical or sub-clinical conditions that canbe remedied by treatment with one or more lipophilic APIs. The mainfeature of such methods is administering to a subject in need thereoftherapeutically effective amounts of compositions and dosage forms ofthe invention.

More specifically, the invention provides methods for treating oralleviating disorders that can be remedied by treatment with lipophilicAPI(s) in a subject in need thereof, wherein the method comprisesadministering to the subject a therapeutically effective amount of asolid water-dispersible composition of matter comprising at least onesugar, at least one polysaccharide and at least one surfactant and atleast one lipophilic API, and wherein the composition comprises aplurality of micrometric particles each comprising a plurality oflipophilic nanospheres with an average size in the range of about 50 nmto about 900 nm, the at least one lipophilic API is contained in themicrometric particles and is distributed inside and/or outside thelipophilic nanospheres at predetermined proportions, thereby providingimmediate and/or prolonged delivery of said lipophilic API (s).

In numerous embodiments said administering of lipophilic API(s) can beoral, sublingual, buccal, rectal, topical, dermal, and transdermaladministering.

In other embodiments said administering of lipophilic API(s) can be viainhalation or nebulization.

In further embodiments said administering of lipophilic API(s) canfurther involve use of a device to facilitate the administering of theAPI(s).

In certain embodiments said administering of lipophilic API(s) can bemade via a sublingual, dermal or transdermal patch of the invention.

In certain embodiments the methods of the invention can further compriseconcomitant administering to the subject least one additional API,lipophilic or not lipophilic.

In numerous embodiments the additional lipophilic APIs can be providedin the compositions of the invention.

These aspects can be further articulated in terms of use of theabove-described compositions in the manufacture of medicaments fortreating or alleviating disorders or conditions that can be remedied bytreatment with lipophilic API(s).

In numerous embodiments the invention provides use of theabove-described compositions in the manufacture of medicaments havingone or more lipophilic APIs with improved bioavailability and/orimproved bio-accessibility.

In yet another aspect, the invention provides a method for making acomposition with increased bioavailability and/or bio-accessibility oflipophilic API(s) by:

-   -   (i) mixing an aqueous phase comprising at least one sugar, at        least one polysaccharide and at least one surfactant with an oil        phase comprising at least one lipophilic API,    -   (ii) emulsifying the mix to obtain a nanoemulsion,    -   (iii) lyophilizing or spray dying the nanoemulsion.

In another aspect, the invention provides a method for increasingloading of at lipophilic API(s) contained in a composition by:

-   -   (i) mixing an aqueous phase comprising at least one sugar, at        least one polysaccharide and at least one surfactant with an oil        phase comprising at least one lipophilic API,    -   (ii) emulsifying the mix to obtain a nanoemulsion,    -   (iii) lyophilizing or spray dying the nanoemulsion.

A specific application of the present technology is to provide anespecially attractive formulation of API(s) in a micronized sugarparticle, which can be further incorporated into various foods,chocolates, and sweets.

Essentially, the invention provides a sugar particle comprising a poroussugar material and lipophilic nanospheres having average sizes betweenabout 50 to about 900 nm so that the lipophilic nanospheres arecomprised within the porous sugar material, the sugar particle furthercomprises at least one edible sugar, at least one edible oil, at leastone edible polysaccharide, at least one edible surfactant and at leastone API.

The term ‘porous sugar material’ is meant to convey a solid sieve-likematerial with voids or pores which are not occupied by the mainstructure of atoms of the solid material (e.g., sugar). This termencompasses herein a material with regularly or irregularly dispersedpores, and pores in the form of cavities, channels, or interstices, withdifferent characteristics of pores size, arrangement, and shape, as wellas porosity of the material as a whole (the ratio of pores volume vs.the volume of solid material) and composition of solid material.

As has been noted, in numerous embodiments the lipophilic nanospherescan have an average size in the range between about 50-900 nm, andspecifically in the range between about 50-100 nm, 100-150 nm, 150-200nm, 200-250 nm, 250-300 nm, 300-350 nm, 350-400 nm, 400-450 nm, 450-500nm, 500-550 nm, 550-600 nm, 650-700 nm, 700-750 nm, 750-800 nm, 800-850nm, 850-900 nm and 900-1000 nm.

In certain embodiments the lipophilic nanospheres can have an averagesize in the range between about 100-200 nm, and specifically in therange between about 100-110 nm, 110-120 nm, 120-130 nm, 130-140 nm,140-150 nm, 150-160 nm, 160-170 nm, 170-180 nm, 180-190 nm and 190-200nm.

In numerous embodiments the size of the sugar particles can be in therange between about 10 μm and about 300 μm, and specifically in therange between about 10-50 μm, 50-100 μm, 100-150 μm, 150-200 μm and250-300 μm or more.

In certain embodiments the size of the sugar particles can be in therange between about 20 μm to about 50 μm, and specifically in the rangebetween about 10-50 μm, 20-50 μm, 30-50 μm, and 40-50 μm, or up to atleast about 20 μm, 30 μm, 40 μm, 50 μm.

Within the indicated size ranges, in numerous embodiments the sugarparticles of the invention can have an irregular shape or form (EXAMPLE11).

In numerous embodiments the edible sugars comprised in the sugarparticles can be obtained from a vegetable or an animal source, asynthetic sugar, or a mixture thereof.

In further embodiments the edible sugars can be obtained from a sugarbeet, a sugar cane, a sugar palm, a maple sap and/or a sweet sorghum.

In certain embodiments the edible sugars can be a mono- and/ordi-saccharides selected from glucose, fructose, sucrose, lactosemaltose, galactose, trehalose, mannitol, lactitol or a mixture thereof.

In numerous embodiments the edible sugars can constitute between bout30% to about 80% of the sugar particle (w/w), or more specificallybetween about 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80% and80%-90% of the sugar particle (w/w).

In numerous embodiments the edible polysaccharides can be selected frommaltodextrins and carboxymethyl celluloses (CMC).

In numerous embodiments the edible surfactants can be selected fromammonium glycyrrhizinate, pluronic F-127 and pluronic F-68.

In numerous embodiments the edible surfactants can be selected from oneor more monoglycerides, diglycerines, glycolipids, lecithins, fattyalcohols, fatty acids.

In certain embodiments the edible surfactants can be sucrose fatty acidesters (sugar ester).

In numerous embodiments the edible oils can be obtained from a vegetableor an animal source, a synthetic oil or fat, or a mixture thereof.

In certain embodiments the edible oils can comprise Theobroma oil (cocoabutter).

In numerous embodiments the sugar particles of the invention can furthercomprise one or more food colorants, taste or aroma enhancers, tastemaskers, food preservatives.

A nonlimiting list of substances applicable to this specific aspect isprovided in ANNEX A.

Thus in this particular aspect, the invention can be perceived as amedical food containing one or more lipophilic APIs dispersed in a foodmatrix. This food matrix may be a traditional food type (such as abeverage, yogurt, or confectionary) or a nutritional fluid fed to apatient through a tube. A medical food is usually administered to treata particular disease under medical supervision.

The invention further provides compositions and method of us foreradicating, preventing development and destruction of microbialbiofilms. Compositions of the invention may be applied to any tissue ororgan in a subject's body by any means disclosed herein to treat orprevent evolution of such biofilms. The biofilms may alternatively aresuch formed on a surface of a device or a tool such as those used inmedical facilities.

The term “about” in all its appearances in the text denotes up to a ±10%deviation from the specified values and/or ranges, more specifically, upto ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9% or ±10% deviationtherefrom.

EXAMPLES

Any methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention.Some embodiments of the invention will be now described by way ofexamples with reference to respective figures.

Example 1: Physical Properties of the Powder Compositions 1.1Preservation of Particle Size in the Reconstituted Compositions

Powder composition comprising 30% of AlaskaOmega (Omega 3) was preparedby nano-emulsification, freezing in liquid N₂ and lyophilization (48 h).Distribution and uniformity of the particle size was evaluated afternanoemulsification and lyophilization upon dispersion of the powder inTWD to 1% (w/w) using PDI (poly dispersity index) measured by DLS(dynamic light scattering). Measurements were perfumed in triplicates.PDI correlates to particle size. PDI values indicated that thenanoemulsion and the reconstituted powder contained a uniform andhomogenous population of particles with the average size of 149 nm±SDand 190 nm±SD, respectively.

The results suggest that the particle size in the reconstituted powdercompositions is relatively constant and preserved relative to the sourcenanoemulsions, and that this feature is uniform and homogeneous persample, overall. The finding of preservation of particle size is furtherindicative of the same trend in saliva and the GI.

1.2 Preservation of Particle Size after Storage for 1 Month

The powders were stored for 1 month, and then reconstituted in TWD to 1%(w/w) or to 2% (w/w) and subjected to DLS or Cryo-TEM (transmissionelectron cryo-microscopy) analyses. The average particle size in thereconstituted powders was 218 nm±SD and 100 nm±S for DLS and Cryo-TEM,respectively, suggesting that the measurements are dependent on thetechnology.

Overall, the results suggest that the powder compositions are relativelystable and preserve that reconstitution capacity of a relatively uniformpopulation of particles at a nanometric range.

1.3 Powder Compositions with Lycopene Oil and Hemp Oil

Powder compositions produced from lycopene oil and hemp (1:1.4,respectively) using the above method. DLS analysis was performed on thenanoemulsion and the reconstituted powder (1% w/w). DLS analysis showeda single population of particles in the nanoemulsion with the averagesize of about 590 nm, and two populations of particles in thereconstituted powder with the average size of about 272 nm and a minorpeak at 79 nm. The particle size was not increased after lyophilization.

The results indicate that in terms of preservation and uniformity ofparticle size, the powder compositions with lycopene and hemp oil behavesimilarly to the powders with Omega 3. Overall, the results suggest thatthe technology is adaptable to various types of lipophilic drugcarriers, i.e., oils and combinations of oils.

1.4 Preliminary Stability Studies in Compositions with Cannabinoids

Powder compositions with CBD or THC were stored at 45° C. (oven) for 1,35, 54, 72 and 82 days (3 months correlates to 24 months at RT).Particle size was evaluated using DLS. The results are shown in Table 1and FIG. 1 .

TABLE 1 DS measurements in test samples Temp AVG PDI PEAK RT 150.5 0.208163.2 1 day at 45° C. 149.1 0.213 151.9 35 days at 45° C. 160.2 0.25159.6 54 days at 45° C. 150.1 0.216 144.7 72 days at 45° C. 150.1 0.212143.3 82 days at 45° C. 153.7 0.205 154 AVG average diameter (nm) PDIpolydispersity index

The results show that the particle size was preserved for at least threemonths at 45° C., thus suggesting that the powder compositions havelong-term stability and ability to preserve particle size uponreconstitution in water solutions, and most likely in the GI.

1.5 Compositions with Lactose and Hemp Oil

Nanoemulsions and the respective powders were prepared with lactose as achoice of sugar. The list of ingredients is detailed in Table 2.

TABLE 2 Specifications of test samples Lactose 80% 90% 100% 110% 120%Ammonium Gly 3.05 3.05 3.05 3.05 3.05 Meltodextrin 13.68 13.68 13.6813.68 13.68 Lactose 16 18 20 22 24 Water 145.74 145.74 145.74 145.74145.74 Hemp oil 15.74 15.74 15.74 15.74 15.74

Nanoemulsions were prepared from lactose solution (80%) and maltodextrin(25-50° C.). Lactose was added to the mix to the concertation of 90%,100%, 110%, 120% (relative to the initial concentration), together withAmmonium Gly and hemp oil. The nanoemulsions were homogenized byM-110EH-30 at 10,000-20,000 PSI (25-50° C.)×4 cycles. Powders wereprepared using (1) lyophilization: freezing (−25° C. to −86° C.) andlyophilization (12-24 h, −51° C., 7.7 mbar); or (2) spray drying: usingperistaltic pump (rate 8.5-20 g/min, air temp. 110-150° C., air flow0.4-0.5 m³/min, atomizer pressure 0.15 MPa). DLS analysis of thereconstituted powders is shown in Table 3.

TABLE 3 DS measurements in tested samples Lactose Drying Yield Pump rateAverage Size conc. technology (%) T air out (g/min) (nm)  80% Spraydryer 54.8 62 8.78 135.3  90% Spray dryer 63.8 62 9.66 127.6 100% Spraydryer 87.5 63 10.4 125.6 120% Spray dryer 87 63 10.1 124.6  80%Lyophilizer 100% NR NR 136.1 100% Lyophilizer 100% NR NR 127.8 110%Lyophilizer 100% NR NR 125.4 120% Lyophilizer 100% NR NR 124.5

The results point to preservation of particles size under variousmanipulations and concentrations of lactose. Overall, the resultssuggest that lactose can serve as an alternative sugar withoutdisrupting the core properties of the compositions.

1.6 Loading Capacity and Distribution of the Lipophilic Component

Nanoemulsions were prepared with various types of oil carriers: Omega 7,TG400300, EE400300. Surface oil content was determined by hexane.Powders (5 g) were washed with hexane (50 ml), filtered, and washed (×4)with hexane (5 ml). Loss on drying (LOD) was performed on the filtrateunder N₂ until stabilization of weight. The oil content inside thenanospheres was estimated as:

-   -   Omega 7-52.67%    -   TG400300-30.67%    -   EE400300-35.33%

The results suggest that up to about 50% lipophilic carrier can beincorporated into the lipophilic nanospheres, depending on the type ofoil. A similar distribution can be assumed for the lipophilic API(s)dissolved in this and other types of carriers.

The results indicate that a substantial proportion of lipophilic carrier(and lipophilic API) can be present outside the nanospheres. Thisfinding strongly supports the notion of differential bioavailability andbiphasic release of the lipophilic APIs characteristic of thecompositions of the invention.

More recent studies suggested that above 80% and 90% of lipophiliccarriers and lipophilic APIs can be incorporated into the nanospheres.

Overall, these results are indicative of high loading capacity oflipophilic carriers and lipophilic APIs in the powder compositions ofthe invention.

1.7 Encapsulation Capacity of the Compositions

Encapsulation capability was estimated by the difference between theinitial amount of API and the final amount unentrapped in thecomposition. Four different types of powders were prepared with thefollowing lipophilic carriers/APIs using the above methods:

-   -   Vitamin D3 oil    -   Passionfruit oil    -   Medium-chain triglyceride (MCT) oil    -   Pomegranate seed oil

The non-encapsulated lipophilic carriers/APIs were removed with hexane(shaking 1 g powder in 10 ml n-Hexane for 2 min), the product wasfiltered and washed with hexane (×3), and the content of the entrappedlipophilic carriers/APIs was measured using Solventextraction-gravimetric method. The results are shown in Table 4.

TABLE 4 The entrapped oil content of tested compositions Before washAfter wash Encapsulation Oil/active (gr/100 gr) (gr/100 gr efficiencyVitamin D 30.57 30.50 99.8% Passion fruit 30.31 29.46 97 2% MCT 29.0628.79 99.1% Pomegranate 29.16 26.11 99.8%

The results suggest a substantially highly loading capacity oflipophilic carriers/APIs into the compositions of the invention to theextent of about 97.0-99.8%.

1.8 Preservation of Particle Size in High Osmolarity Solutions

The feature of preservation of particle size was further studied insaline solution mimicking the osmolarity on the skin. To be compatiblewith the skin, topical formulations are expected to be stable andmaintain their characteristic properties under the conditions of highsalinity—typically 0.5-0.8% NaCl.

Nanometric powders were resuspended (1% w/w) in the saline solution(0.75% NaCl) and TDW. DLS analysis was performed as above. Tests wereperformed in triplicates. The raw data for the distribution of particlesize is given below:

-   -   Water: Z Avg; 164.1 nm, pdi: 0.232, peak1: 175.3 (99.3%), peak2:        3508 (0.7%).    -   Saline Sol.: Z AVG; 158.2 nm, pdi: 0.236, peak1: 154.3 (98.6%),        peak2: 4085 (1.4%).

The results show minor differences in particle size between the salinesolution and water, 158 nm vs. 164 nm, respectively. The resultsindicate that the powder compositions retain their particle size anduniformity in high osmolarity solutions.

Preservation of nanometric size and larger surface area can providedeeper penetration of APIs into the skin and improved efficacy. Overall,this study suggests that the powder compositions of the invention havethe potential to provide unproved preparations for topical delivery oftherapeutic actives.

1.9 Compositions with Additional Lipophilic Carriers

Powders were prepared with various lipophilic carriers using the abovemethods:

-   -   Sample 1—Fish oil FO 1812 Ultra, 50% oil    -   Sample 2—KD-PUR 490330 TG90 Ultra, 30% oil    -   Sample 3—KD-PUR 490330 TG90 Ultra, 50% oil

Particle size was evaluated in the nanoemulsions and the reconstitutedpowders. The particle size remained surprisingly stable in therespective nanoemulsions and reconstituted powders, with an average sizeranging from about 140-160 nm.

In summary, the different compositions showed consistency of particlesize in the transition from nanoemulsion to solid forms. The particlessize remained stable during the drying process, which is highlysurprising in view of increased temperature and drying conditions. Thisexperiment suggests high applicability of the technology for numeroustypes of lipophilic carriers and APIs.

Example 2: Surprising Chemical Stability of Actives

2.1 Stability of Compositions with Cannabis Extracts

Cannabinoids are especially prone to chemical and photolyticdegradation. Nanoemulsions were prepared with full spectrum Cannabis oil(50%) obtained from two Cannabis strains (THC or CBD enriched) and theother core components of the compositions of the invention.

The reconstituted powders yielded the characteristic particle size ofabout 150 nm and the expected cannabinoid spectrum in oil. Powders werestored in aluminum bags in 40° C. chamber under the followingconditions:

-   -   1 gr per bag    -   O₂ scavenger    -   Silica humidifier

The experiment was performed in two independent runs for powders withTHC and CBD enriched extracts (Powder A and Powder B) Cannabinoidanalysis was performed using HPLC at Baseline (0), 30 days, 45 days, and83 days (correlates to 10, 13, 24 months at RT). The results are shownin Tables 5 and 6.

TABLE 5 Cannabinoid analysis in Powder A Analyte content Total (% w/w)THC-Δ-9 CBD CBG CBN cannabinoids T0 2.71 1.05 0.09 0.08 3.93 10 months2.62 1.03 0.09 0.09 3.83 13 months 2.68 1.02 0.07 0.09 3.86 24 months2.62 1.03 0.09 0.09 3.83

TABLE 6 Cannabinoid analysis in Powder B Analyte content Total (% w/w)THC-Δ-9 CBD CBG CBN cannabinoids T0 0.28 3.95 0.01 0.07 4.31 10 months0.28 3.98 0.01 0.02 4.29 13 months 0.27 3.93 0.01 0.09 4.3 24 months0.28 3.98 0.01 0.02 4.29

The results indicate that the compositions of the invention providelong-term stability of APIs, cannabinoids and complex compositions ofcannabinoids, for at least 24 months at RT. The recommended storageconditions should further include aluminum bags with 02 scavenger and/ormoister desiccator.

Overall, under these conditions, the maximum degradation rate did notexceed 2.5% for the entire cannabinoid content and was even lower forspecific cannabinoids (THC and CBD as CBN and CBG). This finding isfurther consistent with the content of CBN (in Powder A for example) asa known marker of cannabinoid degradation.

2.2 Stability of Compositions Comprising Lycopene

Carotenoids are sensitive to increased temperature, pro-oxidativespecies, and acidic pH. Nanoemulsions were prepared with lycopeneoleoresin (6% lycopene w/w) and the other core components of the presentcompositions. Powders (4 gr) were heat-sealed with vacuum in aluminiumbags with moister and oxygen scavengers, and stored for 0, 30, and 90days at RT (25° C.), 4° C. and 40° C. (in duplicates). Products weretested by visual appearance, DLS and HPLC analyses at the indicated timepoints.

Visual analysis indicated that all samples preserved the typicalconfluence texture, and color during the storage period. DLS analysisindicated that the characteristic particle size of 225-272 nm wasrelatively preserved. The results are shown in Table 7. HPLC analysisshowed minimal losses of lycopene during the storage period, i.e., 7%,3%, and 1% for samples stored at RT, 4° C., and 40° C., respectively.

TABLE 7 DLS analysis of compositions with lycopene Storage temperatureTime 0 Time 30 days Time 90 days RT (about 25° C.) 260 nm 225 nm 236 nm 4° C. 272 nm 265 nm 40° C. 246 nm 251 nm

Overall, the results suggest that the present compositions provide anextended shelf life for APIs such as lycopene and protect against theiroxidation and degradation. Extended stability of 90 days at 40° C.corresponds to 2 years at RT. The recommended conditions should furtherinclude aluminum bags with moister and oxygen scavengers.

2.3 Stability of Compositions with Vitamin D3

Powders with vitamin D3 were stored at 40° C./RH 75° C. for 90 days.Vitamin D3 and ethoxy Vitamin D3 degradation products were detected byHPLC. Analytical tests were further validated by an external authorizedlaboratory (Eurofins). The results are shown in Table 8.

TABLE 8 HPLC analysis of compositions with vitamin D3 Vitamin D EurofinsVitamin D degradation product results Vitamin D3 oil 24.14 mg/gr  0.70mg/gr 26.3 mg/gr  Vitamin D3 powder 6.76 mg/gr 0.40 mg/gr 7.7 mg/gr Day1 Vitamin D3 powder 6.60 mg/gr 0.47 mg/gr Duplicate 1 - 6.9 mg/gr Day 90Duplicate 2 -7.4 mg/gr

Cholecalciferol tests were consistent with the certificate (1M iu/g).The results indicated that the encapsulated fraction contained 28%-29%Vitamin D3 compared to the 30% Vitamin D3 in the original oilpreparation, suggesting minimal losses of active during the productionprocess. Further, only minimal degradation was observed during thestorage period (up to 5% API). The differences between duplicates can beexplained by soldering. The powder had far fewer degradation productscompared to the oil form. The study suggested potential stability of thepowder form for a period of 2 years at RT.

The above studies suggest that the powder compositions of the inventionhave surprisingly long shelf-life and capability to preserve chemicalstability of APIs. This feature is highly surprising, especially in viewthat the production process involves high pressure, water environment,both of which are unfavorable for lipophilic molecules, and further inview that reduction of particle size and increased surface area areexpected to increase oxidation and chemical instability of actives.These findings further support pharmacological applicability of thepresent compositions and methods.

2.4 Stability in Compositions with Fish Oil

The protective property of the present powder compositions was furthersupported in a study using compositions with fish oil. Fish oils (60%Omega 3 fatty acids w/w) are known to oxidize readily by forming primaryand secondary oxidation products.

Powder compositions were prepared from 40% fish oil (w/w) and the othercore components. The oil and powder samples were exposed toenvironmental oxygen, heat-sealed with vacuum, and stored at 4° C. for28 days. The primary (peroxide; PV) and the secondary (anisidine; AV)oxidation products were measured at days 0, 14, and 28. TOTOX value(overall oxidation state) was calculated using Formula:

TOTOX=AV+2*PV.

The results are shown in FIG. 2 . The results show that the powdercomposition had a significantly lower TOTOX, i.e., a significantly lowerconcentrations of primary and secondary oxidation products, compared tothe oil form starting from day 0 and up to day 14. The result of day 0is further suggests that the production process of the powders does notlead to degradation, despite the exposure to water and oxygen.

Overall, the results support a surprising capacity of the powdercompositions to protect actives and prevent their oxidation/degradation,most likely due to encapsulation. This property is further consistentwith the previously shown long-term stability characteristic of thepresent compositions.

Example 3: Surprising Loading Capacity

Loading capacity of the powder compositions was further studied incompositions containing concentrated Cannabis oil. Nanoemulsions wereproduced with raw RSO high THC concentrate (1gr) by the above methods.The nanoemulsions and the reconstituted powders yielded particles withthe characteristic size of about 150 nm. The reconstituted powders weresubjected to analysis of cannabinoids using HPLC. Table 9 shows thecalculated vs. actual cannabinoid content.

TABLE 9 The measured and calculated THC content % w/w CalculatedMeasured Δ9-THC 8.945% 8.45% CBG 0.276% 0.24%

The ratio between the calculated and actual content was 94.91%, and86.9% for Δ9-THC and CBG, respectively, suggesting minimal losses ofactives. The proportion of oil carrier relative to the total powdermaterial further suggests a surprisingly high loading capacity oflipophilic carriers and APIs.

Example 4: Surprising Oral Bioavailability of Cannabinoids 4.1Pharmacokinetic Profiles in Plasma

Pharmacokinetic profiles (PK) of the present compositions were evaluatedin a rat model. The study compared APIs release in plasma of two typesof CBD/THC compositions: a powder composition of the invention (LL-P)and the analogous oil form (LL-OIL). The study used the following endpoints:

-   -   i. Mortality and morbidity monitoring—daily.    -   ii. Body weight monitoring—during acclimation and before dosing.    -   iii. Clinical observation—prior to and for 2 h after oral        administration.    -   iv. Blood draws—at timepoints of 15, 30, 45, 60, 90, 120, 240,        420 min and 24 h.    -   v. Termination and organ collection (brain, liver) at 45, 60,        90, 120, 240 min.

The study used classical pharmacokinetic (PK) analyses in animals (N=18)divided into 6 groups (3 animals in each group).

Materials and Methods

Test item I: CBD/THC POWDER (LL-P): LL-CBD-THC 30% oil in powder.

Test item II: CBD/THC OIL (LL-OIL): LL-CBD-THC oil diluted in hemp oil.

Oral doses were prepared as follows: 150 mg LL-P was dissolved in 2.85mg TDW; 45 mg LL-OIL was diluted in 1 ml hemp oil (per animal).

Male rats /18/376/456 g (sex/number/weight) were divided into groups(deviation of ±20% from mean weight in each group) and acclimatized (8days). The study (1 cycle) was conducted in 6 groups (×3 animals and ×3time points). Blood samples were collected at indicated time-points andstored. Group allocation is shown in Table 10. Animals were observeddaily for toxic/adverse symptoms before and after administration. Therewere no findings of morbidity, pain, or distress during the entire studyperiod.

TABLE 10 Group allocation Group Test Dose Dose (N) Item (mg/kg) (ml/kg)Route Bleeding time point 1M LL-P THC 1 Oral 30, 90, (N = 3) 13.5 0 420min 2M CBD 1 15, 60, (N = 3) 15.7 0 240 min 3M 1 0, 45, 120 (N = 3) 0min, 24 h 4M LL-OIL 3 30, 90, (N = 3) 420 min 5M 3 15, 60, (N = 3) 240min 6M 3 45, 120, (N = 3) 24 h

Results

PK profiles of actives (CBD and THC) in plasma released from LL-P andLL-OIL are shown in Tables 11-12 (0-24 h and 0-7 h periods) and FIGS. 3Aand 3B.

TABLE 11 PK analysis for 0-24 h Single Dose CBD CBD THC THC ParametersLL-P LL-OIL LL-P LL-oil Estimated Half-life hr 10.1 7.2 8.9 8.0 C_(max)(obs) ng/ml 82.5 35.8 242.7 103.4 T_(max) (obs) hr 0.75 4.0 0.75 2.0AUC₍₀₋₂₄₎ (obs area) ng-hr/ml 208.8 309.3 900.5 919.1

TABLE 12 PK analysis for 0-7 h Single Dose CBD CBD THC THC ParametersLL-P LL-OIL LL-P LL-oil Estimated Half-life hr 1.6 3.9 1.5 2.9 C_(max)(obs) ng/ml 82.5 35.8 242.7 103.4 T_(max) (obs) hr 0.75 4.0 0.75 2.0AUC₍₀₋₇₎ (obs area) ng-hr/ml 123.3 169.5 574.2 517.8

Conclusions

LL-P showed a significantly more rapid release profile in plasmacompared to LL-OIL, both for CBD (Tmax 0.75 h vs. 4 h) and THC (Tmax0.75 h vs. 2 h; LL-P and LL-OIL respectively). The observed plasma CBDCmax was more than double (82.5 vs. 35.8 ng/mL, LL-P and LL-OILrespectively). The plasma THC Cmax was also significantly higher (242.7vs. 103.4 ng/mL, LL-P and LL-OIL respectively). The oral bioavailabilityas reflected in calculations of AUC (area under curve) was about 40%higher for CBD in LL-oil than in LL-P, but was similar for THC in bothforms.

4.2 Biodistribution in Tissues

Analogous study compared CBD/THC compositions in powder (LL-P) and oil(LL-OIL) forms with regard to release of APIs in plasma and selectedorgans (liver and brain). The study used the above end points, apartfrom:

iv. Blood draws—at timepoints of 0, 15, 30, 45, 60, 90, 120 and 240 min.

The study used classic PK analyses in animals (N=12) divided into 2groups.

Materials and Methods

Test item I: CBD/THC POWDER (LL-P): LL-CBD-THC 30% oil in powder

Test item II: CBD/THC OIL (LL-OIL): LL-CBD-THC oil diluted in hemp oil

Oral doses were prepared as follows: 225 mg of LL-P was dissolved in4.275 mg TDW; 67.5 mg LL-OIL was diluted in 1 ml hemp oil (per animal).

Male rats/12/376/456 g (sex/number/weight) were divided into groups(deviation of ±20% from mean weight in each group) and acclimatized (8days). The study (1 cycle) was conducted in 2 groups (×6 animals, ×3-4time points). Blood samples were collected at indicated time-points andstored. Organs (brain, liver) were collected after terminal bleeding andperfusion, and stored. Variations in organs weight were insignificant.Group allocation is shown in Table 13. There were no findings ofmorbidity, pain, or distress during the entire study period.

TABLE 13 Group allocation Dose Dose volume Group (mg/kg) (ml/kg) RouteAnimal Bleeding time point Termination LL-P THC 10 Oral 1 0, 15, 45 min45 min 13.5 2 0, 30, 60, 240 min 240 min CBD 3 15, 45, 60 min 60 min15.7 4 30, 60, 90 min 90 min 5 45, 90, 120 min 120 min 6 0, 15, 30, 90min 90 min LL- 3 7 0, 15, 45 min 45 min OIL 8 0, 30, 60, 240 min 240 min9 15, 45, 60 min 60 min 10 30, 60, 90 min 90 min 11 45, 90, 120 min 120min 12 0, 15, 30, 90 min 90 min

Results

PK analyses of actives (CBD and THC) in plasma, brain and liver releasedfrom LL-P and LL-OIL are shown in Table 14, and FIGS. 4A-4B (plasma) andFIGS. 5A-5D (liver and brain).

TABLE 14 PK analysis of CBD and THC in plasma, brain and liver CBD CBDTHC THC LL-P LL-OIL LL-P LL-OIL General PK parameters: PLASMA PLASMAPLASMA PLASMA Dose Amount mg 6.5 6.5 5.6 5.6 Dosage mg/kg 15.7 15.7 13.513.5 C_(max) (obs) ng/ml 137.0 156.6 444.4 174.6 T_(max) (obs) hr 4.04.0 4.0 4.0 AUC (0-4) (obs area) ng-hr/ml THC THC CBD CBD LL-P BRAINLL-P BRAIN General PK parameters: BRAIN LL-OIL BRAIN LL-OIL Dose Amountmg 5.6 5.6 6.5 6.5 Dosage mg/kg 13.5 13.5 15.7 15.7 C_(max) (obs) ng/g206.9 115.0 122.6 95.6 T_(max) (obs) hr 1.0 4.0 1.0 4.0 AUC(0-4) (obsarea) ng-hr/g 536.5 215.0 201.0 221.5 THC THC CBD CBD LL-P LL-OIL LL-PLL-OIL General PK parameters: LIVER LIVER LIVER LIVER Dose Amount ng 5.65.6 6.5 6.5 Dosage ng/kg 13.5 13.5 15.7 15.7 C_(max) (obs) ng/g 6828.81289.0 4037.2 1604.9 T_(max) (obs) hr 1.0 4.0 1.0 2.0 AUC(0-4) (obsarea) ng-hr/g 12982.1 3004.1 7306.0 4184.4

Conclusions

In plasma, LL-P showed a biphasic release profile with an immediateincrease of APIs during the first hour, followed by a decrease andanother increase persisting until termination of the study period. Incontrast, LL-OIL showed a monophasic release profile of actives duringthe study period (240 min).

The PK profiles in the liver and brain mimicked the plasma profiles.LL-P showed significantly more rapid permeation of both APIs into thetissues compared to LL-OIL, In the brain, CBD Cmax was higher in LL-Pcompared to LL-OIL (122.6 vs. 95.6 ng/g, respectively), the same wastrue for THC Cmax (206.9 vs. 115 ng/g, respectively). Similar resultswere observed in the liver.

These results suggest that the oral bioavailability of the LL-Pcompositions in plasma and tissues are superior to LL-OIL. Further, LL-Pcompositions can have additional advantage in providing a bi-phasicrelease profile combining immediate as well as prolonged activesrelease.

Example 5: Bioavailability of Compositions with Vitamin D3

Advantageous oral bioavailability of the present compositions wasfurther supported in a study comparing PK plasma profiles ofcompositions with vitamin D3 in powder and oil forms. Nanoemulsions wereprepared as per standard protocol using both, lyophilization and spraydrying. Table 15 shows that the powder compositions maintained thecharacteristic features of particle size, time to dissolution andothers.

TABLE 15 QC test of the powder composition with vit. D3 Vit. D powder QCparameters Powder properties Fine and white Vitamin D3 content % (w/w)300,000 IU/g Particle size-nm (in emulsion) 150-200 nm ExcipientsDisaccharide, polysaccharide, natural emulsifier PH level in emulsion4.4 Time to dissolution (sec) <90 Water content (%) <2 Flowability Bulkdensity 0.5 gr/ml Tap density 0.7 gr/ml Angle of repose 45°

PK analyses were performed in rat plasma (N=9) upon administration of asingle oral dose of cholecalciferol (1 mg/kg body weight). Blood sampleswere collected at 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 32, 48, 56, 72, 80,96 and 104 h (4 days). Steady-state cholecalciferol concentrations inplasma were measured by gas-liquid chromatography. Parameters werecompared after subtraction of Baseline concentrations and using Baselineconcentrations as a covariate. The results are shown in FIG. 6 .

The results indicated that vitamin D3 in the powder composition peakedrapidly reaching at a double concertation in plasma relatively to theoil form, and further remained at a lower steady state concertation forat least 60 h (3 days). The bioavailability of vitamin D3 in the powderform as reflected in AUC (area under curve) was higher by 20%, and thehalf-life was longer by 15% (p<0.05) than in the oil form.

Overall, the results suggest improved oral bioavailability of lipophilicAPIs in the powder compositions of the invention.

Example 6: Enhanced Bio-Accessibility of Actives 6.1 Study In VitroMimicking the Conditions in the GI

The study explored the behavior of two actives, Thymol(2-isopropyl-5-methyl phenol) and Carvacrol (2-methyl5-(1-methylethyl)phenol), found in Oregano oil. Oregano oil is known for its beneficialproperties, including antioxidant, free radical scavenging,anti-inflammatory, analgesic, antispasmodic, antibacterial, antifungal,antiseptic, and antitumor activities. Both these compounds have lowsolubility and permeability due to lipophilic properties and liabilityto degradation in the acidic condition in the stomach.

The study evaluated the bio-accessibility of Thymol and Carvacrol in theoriginal oil form vs. the powder of the compositions of the inventionusing in vitro semi-dynamic digestion model. Bio-accessibility reflectsthe degree of GI digestion, i.e., an amount of compound released in theGI tract and becoming available for adsorption (e.g., enters thebloodstream). This parameter is further dependent on digestivetransformation of the compound and its respective adsorption intointestinal cells and pre-systemic, intestinal, and hepatic metabolism.Bio-accessibility in vitro can be evaluated according to the followingequation:

Bio-accessibility (%)=(Thymol and Carvacrol content after digestion invitro/Thymol and Carvacrol initial content)×100

There are several types of in vitro digestion models: the static,semi-dynamic, and dynamic models. The static model is characterized by asingle set of initial conditions (pH, concentration of enzymes, bilesalts, etc.) for each part of the GI tract. It is relatively simplisticand has many advantages, but often provide a not realistic simulation ofcomplex in vivo processes. The dynamic digestion model, in contrast,further includes corrections for geometry, biochemistry, and physicalforces to better reflect in vivo digestion (e.g., continuous flow of thedigestion content from the stomach to intestine, HCl addition, pepsinflow rate, gastric emptying, and controlled bile secretion). Thesemi-dynamic model is an intermediate model combining the advantages ofboth approaches. It includes pH modulation by HCl in the gastric phaseand NH₄HCO₃ in the intestinal phase (unlike the static model) but has nocontinuous flow of the digestion contents and the intestinal stagebegins after the gastric stage (unlike in the dynamic model).

Materials and Methods

APIs were tested in the forms of: (1) Oregano oil: 365 μl (˜300 mgOregano oil) comprising 1.26 mg Thymol and 26.31 mg Carvacrol; and (2)Oregano powder: 1.11 gr the powder composition of the inventioncomprising 1.30 mg Thymol and 26.31 mg Carvacrol. The powder compositionwas produced according to the above method, yielding loading of 30%Oregano oil (w/w).

The two forms were tested in the semi-dynamic digestion system usingINFOGEST protocol. The concentration of Thymol and Carvacrol wasmeasured at the Baseline and after 2 h (representative of theend-gastric phase). Samples were analyzed by gas chromatography-massspectrometry (GC-MS) using fused silica capillarity column (30 M, 0.25mm), source temperature of 230° C., quad temperature of 150° C., andcolumn oven temperature 250° C. for 3 min. Digesta sample (1 μl) wasinjected and concentration of analytes was calculated (peak area againststandard peak area). The calibration curve showed linearity of the MSresponse. All preparations were analyzed by GC-MS before and after thein vitro gastric digestion at relevant time points. Chemical analysis ofthe oil and powder compositions was performed to assess loss of activesduring powder preparation.

Results

Thymol and Carvacrol concentrations were reduced during the powderpreparation process by 7% and 10%, respectively. In vitro digestionsstudies of the two forms showed that at the end of the gastric phase (2h post-ingestion), the bio-accessibility of Carvacrol was 19% and 41%(more than twice) for the oil the powder forms, respectively. Similarly,the bio-accessibility of Thymol was 16% and 37% for the oil the powderforms. The bio-accessibility of both APIs was 19% and 41% for the oiland powder forms, respectively. In other words, while only about 20%APIs in the oil composition survived the acid pH in the stomach, theAPIs survival in the powder composition was significantly increased. Theresults are shown in FIG. 7 .

Conclusions

Overall, the results suggest that the powder compositions of theinvention can protect actives from gastric degradation, and therebyincrease their oral bioavailability and bio-accessibility to thecirculation and tissues.

6.2 Comparative Study Including Powders in Enteric-Coated Capsules

Analogous study was performed, including the oil and powder forms asabove and the powder form in enteric-coated capsules (acid resistantcoating). Thymol and Carvacrol concentrations were measured at Baselineand after 2 h (end of gastric phase), with calculations ofbio-accessibility as above. In addition, the powder in enteric-coatedcapsules was shifted from the stomach phase to the duodenal phase andtested after 4 h (end of duodenal phase).

Results

The bio-accessibility of Thymol and Carvacrol at the end of the gastricphase was 19%, 41% and 89% for the oil and powder forms and the powderin enteric coated capsules, respectively, suggesting significantdifferences between various types of compositions. Similar results wereobtained for the separate actives. For Thymol for example, thebio-accessibility was 16%, 37% and 87%, respectively. The results areshown in FIGS. 8A-8C. The bio-accessibility of the powder in entericcoated capsules at the end of the duodenal phase was 79% (for bothactives). The result are shown in FIG. 8D. The bio-accessibility ofCarvacrol was 78% and Thymol 97%.

Conclusions

The results suggest that the protective effect of the powdercompositions can be further enhanced by the addition of functionalcoating, thereby increasing even further their gastric and duodenalbio-accessibility.

Overall, the invention provides a highly relevant pharmaceuticalsplatform for formulating poorly water-soluble APIs to achieve improvedoral bioavailability and bio-accessibility of incorporated actives.

Example 7: Compositions Incorporated into PVA Films

7.1 Compositions Incorporated into a Sublingual Patch

The experiment explored application of the technology to PVA sublingualfilms. Powders containing 30-50% oil were reconstituted in TDW to 5%(w/w). PVA solution (4.5%) was prepared from PVA powder (86-89hydrolyzed PVA) in TDW. PVA solution was mixed with the nanoemulsion inproportions of 4% and 0.5%, respectively. Samples (3 g, ×6 samples) werecasted into aluminum mold and dried at 38° C. for 24 h. Some samplesincluded flavoring agents. Samples' specifications are detailed in Table16.

TABLE 16 Specifications of the sample Nanoemulsion Actual PVA Sample Dry#sample addition (g) conc. size (g) weight (g) 1 8.0% 2.5 0.20 2 2.17.6% 4.2 0.34 3 2.1 7.3% 4.2 0.32 4 2.1 6.9% 4.2 0.31 5 2.1 6.6% 4.20.28 6 2.1 6.3% 4.2 0.30

All samples produced films, the differences in shape can be attributedto different wetting properties. Table 17 shows comparison between theactual dry weight and theoretical weight, suggesting a completeevaporation of water during drying. The nanoemulsion was uniformlydispersed across the films.

TABLE 17 Estimates of the actual and theoretical weight Nano-particlesPVA theoretical theoretical Total theoretical Actual dry content (g)content (g) dry compounds (g) weight (g) 0.20 0.000 0.20 0.20 0.32 0.0080.33 0.34 0.31 0.017 0.32 0.32 0.29 0.025 0.32 0.31 0.28 0.034 0.31 0.280.26 0.042 0.31 0.30

Selected samples (N=3) were dissolved in 50 ml TDW at 37° C. for 20-40min. Sample 6 (dry weight 0.15 g) was analyzed for oil content, yieldingabout 0.017 g oil—83.6% of the theoretical content. The produced film(1*1 cm², ˜100 μm thick) was placed under the tongue measuring the timeto complete dissolution.

The results suggest that the powder of the invention was suitable forformulation in polymeric films. The solid particles were evenly fixed inthe polymerized film to create a solid-in-solid dispersion. Upondissolution, the particles were completely released from the PVA matrix.Overall, a sub-lingual film provides an attractive approach for oral andtransmucosal delivery of certain type of lipophilic APIs.

7.2 Compositions Incorporated into a Dermal and Transdermal Patch

Powders containing 30-50% oil were reconstituted in TDW to 0.5% (w/w).PVA solution (8%) and PVA/nanoemulsion mix were prepared as above,casted into aluminum mold and dried. Samples' specifications weresimilar (see Table 16). The produced film (2*1 cm², ˜100 μm thick) wasdissolved in TDW at 37° C. and analyzed for oil content. Estimates ofparticles size before and after release from the film are show in Table18.

TABLE 18 Estimates of particle size Average particle size in Averageparticle size #sample the pre-formulation after release from PVA 1 187nm 207 nm 2 187 nm 210 nm 3 187 nm 208 nm 4 187 nm 214 nm 5 187 nm 202nm 6 187 nm 202 nm

Nanometric particle size has a significant impact on the surface area ofAPI and its permeation rate through biological membranes. In view ofthat, the finding that the particle size was maintained in the PVAformulations is particularly important; this is despite the exposure topolar environment (PVA film), temperature and drying. Upon drying, thesolid particles were evenly fixed in the polymerized film to create asolid-in-solid dispersion. Stability of this structure can be attributedto the unique nanoparticulate nature of the present compositions. Upondissolution, the particles were completely released from the polymer.

Overall, the results suggest that the present powder compositions can beincorporated into pharmaceutical dosage forms such as dermal films, thusproviding an attractive innovative approach to dermal and transdermaldelivery of actives. The natural humidity of the skin causes the film todissolve slowly, thereby slowly releasing the nanoparticulate lipophilicactives embedded in the film until complete dissolution of the film andpermeation of actives through the epidermal layers into the circulation.All these make dermal patches a particularly advantageous dosage formfor prolonged delivery of actives through the skin.

Example 8: Enhanced Permeability Through the Skin

Permeability through the skin was studied with compositions containingVitamin A and CBD comparing the respective powder and oil forms in exvivo model of human skin. The results are shown in FIG. 9 and FIGS.10A-10C.

The results suggest that the powder compositions of the invention have asignificantly enhanced permeation through the various layers of humanskin compared to the respective oil forms. For vitamin A for example,the permeability through the full-thickness of human skin was 6-foldhigher for the powder compositions than for the respective oil forms(FIG. 9 ). For CBD, the permeability of the powder form was higherthrough the 1St outermost layer of the stratum corneum, and about 4-foldhigher through the 2nd layer of the stratum corneum (FIG. 10A), yieldingabout 10-fold higher concertation of API in the epidermis overall (FIG.10B) and significantly higher rate cumulative transport of API into thedeeper layers of the skin (FIG. 10C).

Example 9: Compositions in the from of Mist (Nebulizer)

An attractive method of administration, especially for certain types ofAPIs, is via an inhalation device or a nebulizer. To that end, thepowder compositions were loaded into a nebulizer for home-use and theproduct was analyzed for particle size and other characteristicproperties. Powder containing 30-50% oil (example of lipophilic API) wasdissolved in TDW to the concentration of 20% to produce nanoemulsion,which was diluted to 10%, 4%, 2% and 1%. Samples' specifications aredetailed in Table 19.

TABLE 19 Measurements of particle size Run Residual Conc API DDW timeamount Nanoemulsion (%) API source amount units (ml) (min) (g) A 20LL-C:H 4 g 20 8:37 0.39 1:10 5-1-20 A 20 LL-C:H 4 g 20 7:10 0.71 1:105-1-20 B 10 Nanoemulsion A 10 ml 10 7:53 0.49 C 4 Nanoemulsion B 8 ml 127:30 0.49 D 2 Nanoemulsion C 10 ml 10 12:25  0.54 E 1 Nanoemulsion D 10ml 10 8:43 0.60 Water 0 NA NA NA 2 12:00  0.56

Samples of the nanoemulsions (2 ml) and water control were loaded intothe device. Nanoemulsion A was subjected to two runs for comparison.Upon activating the device, the mist was clearly visible for therecorded period. Residual nanoemulsion was visible on the device walls.The inhalation cup was weighed on a lab scale (0.01 g precision) beforeand after each test and residual weight was calculated.

The residual amount ranged from 0.39 to 0.71 gr. (17.7%-32.2%), with theaverage of 0.54 g. (about 25.4%). The nanoemulsion s.g ranged from1.01-1.08 g/ml, depending on the concentration of the nanoemulsion, withthe average residual amount similar to the distilled water.

Overall, the results suggest that reconstituted powder compositions canbe used in nebulizers to produce a particulate nanometric material inthe form of mist that is inhalable into to the respiratory tract. Theeffectiveness of mist production from the nanoemulsion was equivalent towater.

Example 10: Compositions with Antibiotics

The study investigated the potential of encapsulating clarithromycin, anantibiotic against Pseudomonas aeruginosa, into the compositions of theinvention. P. aeruginosa is the primary pathogen in the lungs of cysticfibrosis patients. This strain of bacteria is known for its ability toform biofilm, on biotic and abiotic surfaces, which makes itparticularly resistant to host immune defenses and current antibiotictherapies. Clarithromycin, a new semisynthetic macrolide, is lipophilicmolecule that exhibits a broad spectrum of antimicrobial activityagainst Gram-positive and -negative aerobes.

Compositions with clarithromycin were prepared by cold physical process.Powder clarithromycin compositions were dissolved in water to obtainingnanoemulsion. The control free clarithromycin was dissolved in 1% DMSO.Emulsion dried using lyophilization. Samples were tested in threeindependent experiments, with triplicate in each experiment. Particlesize was measured using DLS. MIC data (minimum inhibitionconcentrations) of the formulated and free antibiotic were compared.

The results showed that powder compositions with the antibiotic retainedits characteristic physical properties, including the nanometricparticles size of about 180 nm (average diameter). Specifications of thenanoemulsion and the MIC data are summarized in Tables 20 and 21.

TABLE 20 Measurements of particle size Clarithromycin powder Fine grantwhite powder composition Particle size (nanoemulsion) 150-200 nmExcipients Disaccharide, polysaccharide, natural emulsifier pH(nanoemulsion) 4.4 Time to dissolution <90 Water content <2

TABLE 21 MIC in the powder and oil compositions Powder composition withclarithromycin Free clarithromycin 0.03125%. 0.0625%

The results show that P. aeruginosa, a highly resistant strain, was moresusceptible to the powder composition with the antibiotic than to thefree form, with MIC 0.03125% mg/liter for the powder compositioncompared to 0.0625% for the free form (P<0.001). In other words, theresults suggest that the effective dose of clarithromycin for achievingsignificant inhibition (50%) of P. aeruginosa the growth and expansionis lower for the powder compositions with clarithromycin compared to thefree form of the same antibiotic.

Overall, the result show significantly increased susceptibility of P.aeruginosa to the powder compositions with clarithromycin (50%, P<0.05),thus proving the applicability of the present technology to enhance theefficacy of known lipophilic antibiotics against pathogenic bacteria,including highly resistant strains.

The results further suggest that the powder compositions may have theability to disrupt and/or enhance the permeability of active through thebacterial biofilm. The powder compositions are essentially dispersedemulsifier-coated negatively charged lipid droplets. The presentfindings of increase efficacy of the drug can be explained by (1) thesmall particle size provides benefits for penetration of the drug andits accumulation in the bacterial biofilm; (2) the negatively chargednanoparticles are generally known to penetrate more easily into thebiofilms; (3) diffusion coefficient depends on drug interaction with theEPS bacterial matrix constructing the biofilm.

In other words, the powder clarithromycin compositions have thepotential to enhance absorption and accumulation of antibiotic activesin microbial biofilms, most likely due to the improved solubility of theemulsified lipid particles. Thus, the present technology provides a newplatform for formulation of lipophilic antibiotics and develop-ment ofnew antimicrobial agents and delivery systems targeting microbialbiofilms.

Example 11: Formulations in Micronized Sugar Particles 11.1 MicronizedSugar Particles

Using the present technology, an example formulation of micronized sugarwas prepared from sucrose, maltodextrin, sugar ester (SP30) andTheobroma oil. The amounts and the proportions of ingredients aredetailed in Table 22. An example protocol of the production process isdetailed further below.

TABLE 22 Amounts and concentrations of ingredients Total Concentrationin the dry Ingredient amount (gr)* formulation (% w/w) Sucrose 610 61Maltodextrin 150 15 Sugar ester (SP30) 40 4 Theobroma oil 200 20 Addedwater (DDW) 2200 NR *Total dry weight of all ingredients: 1000 grEssential steps in the process of making the formulation:

-   -   i. Sucrose and maltodextrin were mixed with DDW.    -   ii. Sugar ester (Sp30) was added, the solution was heated to        50° C. complete dissolution of ingredients.    -   iii. Theobroma oil was added, the solution was homogenized to        produce uniform emulsion.    -   iv. The emulsion was fed to High Pressure Microfluidizer (4 bar,        16,000 PSI ×3 cycles), yielding nanodrops in the size range of        about 100 nm-200 nm.    -   v. The nanoemulsion was frozen (−30° C.) and lyophilized until        completely dry (about 2 days at 0.04 mBar). Alternatively, the        frozen nanoemulsion was spray dried at about 190° C.

The powder product was analyzed by Scanned Electron Microscope (SEM).Images of the product in FIGS. 11A-1B show a smooth finely granulatedsugar particles with size in the range of 20-50 μm. Overall, the resultsshow that the sugar powder of the invention was relatively uniform interms of texture and size, with smooth and finely granulated particlesbelow 50 μm.

11.2 Entrapment of Nanometric Oil Drops in the Sugar Particle

The sugar particles with vitamin E oil (example of lipophilic API) wereanalyzed using Cryogenic Transmission Electron Microscopy (cryo-TEM).Samples were prepared in Controlled Environment Vitrification System(CEVS) with humidity at saturation to prevent evaporation of volatilesand temperature of 25° C. The solution (1 drop) was placed oncarbon-coated perforated polymer film supported on 200 mesh TEM grid.The drop was converted to a thin film (<300 nm) by removing excesssolution. The grid cooled in liquid ethane at −183° C. Cryo-TEM imagingwas performed on Thermo-Fisher Talos F200C at 200 kV. Micrographs wererecorded by Thermo-Fisher Falcon camera (4k×4k resolution). Samples wereexamined in TEM nanoprobe mode using volta phase plates. Imaging wasperformed at low dose mode and acquired by TEM TIA software.

Images of cryo-TEM sections in FIGS. 10A-10D show a population of smoothsurfaced spherical nano-droplets with the average size in the range ofabout 80-150 nm, which is entrapped in the sugar particle.

ANNEX A

A1. Classes of therapeutic agents relevant to the present compositions

-   -   Analgesics including non-narcotic and narcotic analgesics    -   Antacids    -   Antianxiety Drugs    -   Antiarrhythmics    -   Antibacterial agents    -   Antibiotics including naturally occurring, synthetic,        broad-spectrum antibiotics    -   Anticoagulants and Thrornbolytics for arterial or venous        thrombosis    -   Anticonvulsants    -   Antidepressants including mood-lifting antidepressants:        tricyclics, monoamine oxidase inhibitors, and SSRIs    -   Antidiarrheals including antidiarrheal preparations and drugs        that slow down the contractions of the bowel muscles    -   Antiemetics    -   Antifungals including infections that affect hair, skin, nails,        mucous membranes    -   Antihistamines    -   Antihypertensives including diuretics, beta-blockers, calcium        channel blocker, ACE (angiotensin-converting enzyme) inhibitors    -   Anti-Inflammatories    -   Antineoplastics    -   Antipsychotics Also major tranquilizers    -   Antipyretics    -   Antivirals including treatment and temporary protection against        viral infections    -   Barbiturates (see sleeping drugs).    -   Beta-Blockers    -   Bronchodilators    -   Cold Cures in relations to aches, pains, and fever that        accompany a cold    -   Corticosteroids in the context of immunosuppression,        malignancies or deficiency disorders    -   Cough Suppressants including narcotic and non-narcotic        suppressants    -   Cytotoxics as antineoplastics and also as immunosuppressives    -   Decongestants    -   Diuretics    -   Expectorant    -   Hormones: including synthetic equivalents and natural hormone        extracts    -   Hypoglycemics (Oral)    -   Immunosuppressives    -   Laxatives    -   Muscle Relaxants including those that relieve muscle spasm and        minor tranquilizers    -   Sedatives    -   Sex Hormones (Female) including those used for menstrual and        menopausal disorders, oral contraceptives, and also for treating        female and male cancers.    -   Sex Hormones (Male) including those used for male hormonal        deficiency in hypopituitarism or disorders of the testes, also        for treating cancer, and anabolic steroids    -   Sleeping Drugs    -   Tranquilizer including minor and major tranquilizers    -   Vitamins        A2. Nutrient rich oils relevant to the present compositions

Major Pharmaceutically Acceptable Oils

-   -   Coconut oil, an oil high in saturated fat    -   Corn oil, an oil with little odor or taste    -   Cottonseed oil, an oil low in trans-fats    -   Canola oil, (a variety of rapeseed oil)    -   Olive oil    -   Palm oil, the most widely produced tropical oil    -   Peanut oil (ground nut oil)    -   Safflower oil    -   Sesame oil, including cold pressed light oil and hot-pressed        darker oil    -   Soybean oil, produced as a byproduct of processing soy meal    -   Sunflower oil

Other Pharmaceutically Acceptable Oils

-   -   Almond oil    -   Cashew oil,    -   Hazelnut oil    -   Macadamia oil, has no trans-fats, and a good balance        omega-3/omega-6    -   Pecan oil    -   Pistachio oil    -   Walnut oil

Nutrient Rich Oils

-   -   Amaranth oil, high in squalene and unsaturated fatty acids    -   Apricot oil    -   Argan oil, a food oil from Morocco    -   Artichoke oil, extracted from the seeds of Cynara cardunculus    -   Avocado oil    -   Babassu oil, a substitute for coconut oil    -   Ben oil, extracted from the seeds of Moringa oleifera    -   Borneo tallow nut oil, extracted from the fruit of Shorea    -   Buffalo gourd oil, extracted from the seeds of Cucurbita        foetidissima    -   Carob pod oil (Algaroba oil)    -   Coriander seed oil    -   False flax oil made of the seeds of Camelina sativa    -   Grape seed oil    -   Hemp oil, a high quality food oil    -   Kapok seed oil    -   Lallemantia oil, extracted from the seeds of Lallemantia iberica    -   Meadowfoam seed oil, highly stable with over 98% long-chain        fatty acids    -   Mustard oil (pressed)    -   Okra seed oil, extracted from the seed of Hibiscus esculentus    -   Perilla seed oil, high in omega-3 fatty acids    -   Pequi oil, extracted from the seeds of Caryocar brasiliensis    -   Pine nut oil, an expensive food oil from pine nuts    -   Poppyseed oil    -   Prune kernel oil, a gourmet cooking oil.    -   Pumpkin seed oil, a specialty cooking oil    -   Quinoa oil, similar to corn oil    -   Ramtil oil, pressed from the seeds of Guizotia abyssinica (Niger        pea)    -   Rice bran oil    -   Tea oil (Camellia oil)    -   Thistle oil, pressed from the seeds of Silybum marianum.        A3. Other substances relevant to the micronized sugar        formulations

Natural Sugars

-   -   Beet sugar, white and granulated sugar    -   Cane sugar, white refined or brown sugar    -   Brown sugar, granulated cane sugar that has molasses (dark and        light brown)    -   Demerara sugar, a type of raw cane sugar    -   Fructose, fruit sugar twice as sweet as refined cane sugar    -   Fruit sweetener (liquid and solid) made from grape juice        concentrate blended with rice syrup    -   Jaggery (palm sugar, gur), made from the reduced sap of either        the sugar palm or the palmyra palm    -   Maple sugar, much sweeter than white sugar and has fewer        calories    -   Muscovado (Barbados) sugar, a raw cane sugar similar to brown        sugar    -   Piloncillo (panela, panocha), another type of a raw cane sugar    -   Rock sugar (Chinese rock sugar), a lightly caramelized cane        sugar    -   Sucanat: juice from organically grown sugarcane turned into        granular sugar    -   Turbinado sugar, raw cane sugar crystals derived from sugarcane    -   White refined sugar (granulated sugar, table sugar, sucrose)        derived from sugarcane or sugar beets

Edible Polysaccharides

-   -   Starch, generally a polymer consisting of two amylose (normally        20-30%) and amylopectin (normally 70-80%) primarily found in        cereal grains and tubers like corn (maize), wheat, potato,        tapioca, and rice    -   Kaempferia rotunda and Curcuma xanthorrhiza essential oils that        are enriched in cassava starch-based polysaccharide    -   Maltodextrin, a polysaccharide produced from vegetable starch    -   Alginate, a naturally occurring anionic polymer obtained from        brown seaweed, also used in various pharmaceutical preparations        such as gaviscon, bisodol, and asilone    -   Carrageenans, water-soluble polymers with a linear chain of        partially sulfated galactans    -   Pectins, a group of plant-derived polysaccharides    -   Agars, hydrophilic colloids that have the ability to form        reversible gels    -   Chitosan, a promising group of natural polymers with        characteristics such as biodegradability, chemical inertness,        biocompatibility, high mechanical strength    -   Gums, edible-polymer preparations used for their texturizing        capabilities    -   Certain cellulose derivative forms, predominantly four are used        in the food industry: hydroxypropyl cellulose (HPC),        hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose        (CMC), or methylcellulose (MC).

Food Emulsifiers

-   -   lecithin and lecithin derivatives    -   glycerol fatty acid esters    -   hydroxycarboxylic acid and fatty acid esters    -   lactylate fatty acid esters    -   polyglycerol fatty acid esters    -   ethylene or propylene glycol fatty acid esters    -   ethoxylated derivatives of monoglycerides

Natural and Nature-Identical Colorants Allowed in the EU and the USA

-   -   Curcumin (Turmeric    -   Riboflavin    -   Cochineal, Cochineal extract, carminic acid, carmines    -   Chlorophyll(in)s copper complexes chlorophyll(in)s    -   Caramel    -   Vegetable carbon    -   Carrot oil, β-carotene    -   Annatto, bixin, norbixin    -   Paprika extract    -   Lycopene    -   β-Apo-8′-carotenal    -   Ethyl ester of β-apo-8′-carotenoic acid    -   Lutein    -   Canthaxanthin    -   Beetroot red    -   Anthocyanins    -   Cottonseed flour    -   Vegetable juice    -   Saffron

Acidulants and other preservatives

-   -   Lactic acid, acetic acid and other acidulants, alone or in        conjunction with other preservatives such as sorbate and        benzoate    -   Malic and tartaric (tartric) acids    -   Citric acid    -   Ascorbic acid/vitamin C, isoascorbic isomer, erythorbic acid and        their salts

Lipophilic Food Preservatives

-   -   Benzoic acid in the form of its sodium salt    -   Sorbic acid and potassium sorbate, specifically for mold and        yeast inhibition    -   Lipophilic arginine esters, a more recent group of compounds

1. A solid water-dispersible composition of matter comprising at leastone sugar, at least one polysaccharide and at least one surfactant andat least one lipophilic active pharmaceutical ingredient (API), thecomposition comprises a plurality of micrometric particles eachcomprising a plurality of lipophilic nanospheres with an average size inthe range of about 50 nm to about 900 nm, the at least one lipophilicAPI is contained in the micrometric particles and is distributed insideand/or or inside and outside the lipophilic nanospheres at predeterminedproportions, thereby providing an improved delivery of the at least onelipophilic API, wherein the composition has a loading capacity of the atleast one lipophilic API up to about 50% (w/w) relative to total weight,and/or an encapsulation capacity of the at least one lipophilic API inthe range of between about 70% and about 98%. 2-8. (canceled)
 9. Thecomposition of claim 8, wherein the micrometric particles have anaverage size between about 10 μm and to about 300 μm.
 10. (canceled) 11.The composition of claim 1, wherein the size of lipophilic nanospheresis substantially maintained upon dispersion in water.
 12. Thecomposition of claim 1, wherein the at least one lipophilic API isdissolved in at least one pharmaceutically acceptable oil. 13-15.(canceled)
 16. The composition of claim 12, wherein the at least onepharmaceutically acceptable oil is a natural oil, a synthetic oil, amodified natural oil, or a combination thereof.
 17. The composition ofclaim 12, wherein the at least one pharmaceutically acceptable oilselected from acylglycerols, mono- (MAG), di- (DAG) and triacylglycerols(TAG), medium-chain triglycerides (MCT), long chain triglycerides (LCT),saturated or unsaturated fatty acids.
 18. (canceled)
 19. The compositionof claim 1, wherein the at least one sugar is selected from oligo,mono-, di-saccharides and polyols, optionally trehalose, sucrose,mannitol, lactitol and lactose.
 20. The composition of claim 1, whereinthe at least one polysaccharide is selected from maltodextrin andcarboxymethyl cellulose (CMC).
 21. The composition of claim 1, whereinthe at least one surfactant is selected from ammonium glycyrrhizinate,pluronic F-127 or pluronic F-68.
 22. The composition of claim 1, whereinthe at least one surfactant is selected from a natural emulsifier, amonoglyceride, a diglycerine, a glycolipid, a lecithin, a fatty alcohol,a fatty acid or a mixture thereof.
 23. The composition of claim 1,wherein the at least one surfactant is a sucrose fatty acid ester (sugarester).
 24. (canceled)
 25. (canceled)
 26. The composition of claim 1,wherein the at least one lipophilic API is selected from enzymeinhibitors, receptor antagonists or agonists, proton-pump inhibitors,ion-channel inhibitors, and/or reuptake inhibitors.
 27. The compositionof claim 1, wherein the at least one lipophilic API is selected fromantibiotics, antifungal agents, antiviral agents, neuroleptics,analgesics, hormones, anti-inflammatory drugs, non-steroidalanti-inflammatory drugs, anti-rheumatic, drugs anticoagulants,beta-blockers, diuretics, anti-hypertension drugs, anti-atherosclerosisdrugs, antidiabetics, anti-asthmatic drugs, decongestant and/or coldmedicines.
 28. (canceled)
 29. The composition of claim 1, wherein theimproved delivery of the at least one lipophilic API comprises animproved oral bioavailability of the at least one lipophilic API inplasma or at least one tissue, said at least one tissue being at leastone tissue of the central nervous system (CNS), least one lymphatictissue, or at least one tissue of a part of the GI lumen, or the livertissue.
 30. (canceled)
 31. The composition of claim 1, wherein theimproved delivery of the at least one lipophilic API comprises animproved bio-accessibility of the at least one lipophilic API into atleast a part of the gastrointestinal (GI) tract or at least one tissuein the GI tract.
 32. The composition of claim 1, further comprising apharmaceutically acceptable carrier and/or excipient.
 33. Thecomposition of claim 32, the composition being adapted for oral,sublingual, buccal administrations, or rectal, topical, dermal, ortransdermal administrations, or inhalation or nebulization. 34-39.(canceled)
 40. A dosage form comprising a therapeutically effectiveamount of the composition of claim 1, and further optionally comprisinga coating, a shell, or a capsule. 41-51. (canceled)
 52. A method forimproving oral bioavailability and/or bio-accessibility of at least onelipophilic API in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of asolid water-dispersible composition of matter comprising at least onesugar, at least one polysaccharide and at least one surfactant and atleast one lipophilic active pharmaceutical ingredient (API), thecomposition comprises a plurality of micrometric particles eachcomprising a plurality of lipophilic nanospheres with an average size inthe range of about 50 nm to about 900 nm, the at least one lipophilicAPI is contained in the micrometric particles and is distributed insideor inside and outside the lipophilic nanospheres at predeterminedproportions, thereby providing an improved delivery of the at least onelipophilic API, wherein the composition has a loading capacity of the atleast one lipophilic API up to about 50% (w/w) relative to total weight,and/or an encapsulation capacity of the at least one lipophilic API inthe range of between about 70% and about 98%. 53-55. (canceled)
 56. Amethod for treating or alleviating a disorder or a condition that can beremedied by treatment with least one lipophilic API in a subject in needthereof, the method comprises administering to the subject atherapeutically effective amount of a solid water-dispersiblecomposition of matter comprising at least one sugar, at least onepolysaccharide and at least one surfactant and at least one lipophilicactive pharmaceutical ingredient (API), the composition comprises aplurality of micrometric particles each comprising a plurality oflipophilic nanospheres with an average size in the range of about 50 nmto about 900 nm, the at least one lipophilic API is contained in themicrometric particles and is distributed inside or inside and outsidethe lipophilic nanospheres at predetermined proportions, therebyproviding an improved delivery of the at least one lipophilic API,wherein the composition has a loading capacity of the at least onelipophilic API up to about 50% (w/w) relative to total weight, and/or anencapsulation capacity of the at least one lipophilic API in the rangeof between about 70% and about 98%. 57-77. (canceled)